IL25766A - 3-hydroxymethyl-4-(indol-3-yl)-hexahydro-1h-azepines and process for their preparation - Google Patents
3-hydroxymethyl-4-(indol-3-yl)-hexahydro-1h-azepines and process for their preparationInfo
- Publication number
- IL25766A IL25766A IL25766A IL2576666A IL25766A IL 25766 A IL25766 A IL 25766A IL 25766 A IL25766 A IL 25766A IL 2576666 A IL2576666 A IL 2576666A IL 25766 A IL25766 A IL 25766A
- Authority
- IL
- Israel
- Prior art keywords
- alkyl
- carbon atoms
- hydrogen
- formula
- alkoxy
- Prior art date
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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
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- 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)
Description
C O H E N Z E D EIKD & S P I S B A C H R E G D. PATE NT A TTOR N EYS 24, LEVONTIN STR., P. O. B. 1169 I E L - AV I V P A T E N T S & D E S I G N S O D I N A N C E 15379/66 SPECIFICATION 3-HYDROXYMETHYL- -(INPOL--3-YL)-HEXAHYDRO-IH-AZEPINES AND PROCESS FOR THEIR PREPARATION.
We THE UPJOHH CO PAHY, a corporation organised and existing under the laws of the State of Delaware, of 301 Henrietta Street, Kalamazoo, State of Michigan, U.S.A ·, DO HEREBY DECLARE Ihe nature of this invention and in what manner the same is to be performed to be particularly described and ascertained in and by the following statement: This invention relates to novel 3-hydroxymethyl -4-(indol-3-yl )-hexahydro-lH-azepines and to processes for makl the same.
The novel 3-hydroxymethyl -4- ( indol ->-yl ) -hexa hydro- 1H-azepines of the present invention can be represented by the following formula: wherein R, R3, and R4 are hydrogen or alkyl of not more than 4 carbon atoms, and R2 is hydrogen, alkyl of not more than carbon atoms, alkoxy of not more than 4 carbon atoms, or halogen. Examples of alkyl of not more than 4 carbon atoms are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secondary butyl, and tertiary butyl. Examples of alkoxy are methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, secondary butoxy, and tertiary butoxy. Examples of halogen are fluoro, chloro, and bromo.
The 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. When R is alkyl t e 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, f 1 uos i 1 i ci c ■ acid, picric acid, Reinecke's acid, azobenzenesul fon i c acid, palmitic acid, acetic acid, maleic acid, and cycl ohexanesul fami c 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, 2 *320 and 2,6o6,155> are useful as pickling inhibitors, and the fluo-silicic acid addition salts are useful as mothproofing agents according to U. S. Patents 1,9 5,33 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 hal ide, 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. These fluosilicic acid salts can be formed by metathesis of a quaternary ammonium salt with an inorganic fluosilicate 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.
Higher quaternary ammonium salts, as are obtained as described above by using alkyl hal ides 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 formul wherein R, R2, R3, and R4 are as given above, and x is alkyl, for example, methyl, ethyl, propyl, butyl, and the isomeric forms thereof. The 1 i thi urn al umi num hydride reduction can be effected in the manner already known in the art using, for example, ether, dioxane, or tetrahydrof uran as an inert sol- vent.
The start i ng compounds or intermediates of Formula I I can be prepared by reacting with dialkyl malonate, for example, diethyl malonate, a compound of the following formula: wherein R, R2, R3, and R4 are as given above. The reaction is carried out in the presence of a strong base, for exampl sodium hydroxide, and in an inert solvent, for example, xylene. Other suitable strong bases include sodium, sodium hydride, and potassium hydroxide. Other suitable inert solvents include toluene, chl orobenzene, and decahydronaphthal ene. 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 I I are obtained. These isomers can be separated by chromatography and/or fractional crystallization, i f des i red, and both isomers on reduct ion wi th lithium aluminum hydride yield compounds of the invention. It is not necessary, however, to effect a separation because mixtures of the two isomers as crude reaction products can be reduced with lithium aluminum hydride to give the compounds of the i nvent ion.
The starting 3- (2-pyr rol i di nyl ) i ndol es of Formula II I can be prepared by processes already known in the art, for example, Youngdale et al., J. Med. Chem. 7, 415 (1964).
Typical 3- (2-pyr rol id i nyl ) i ndol es which can be thus prepared and which can be used as starting compounds for the process of the invention include 3- (2-pyr rol i d i nyl ) i ndol e, 1-methyl -3- (2-pyrrol idi nyl ) indole, 3- (l-methyl -2-pyrrol idinyl )-indole, 3- (l-ethyl -2-pyr rol i d i nyl ) i ndol e, 1-methyl -3- (1-methyl -2-pyrrol idi nyl ) i ndol e, 5-methyl -3- (l-methyl -2-pyr rol i d i nyl )-indole, 7-methyl -3- (1-methyl -2-pyrrol idi nyl ) i ndole, 5-methoxy-3- (1-methyl -2-pyrro1idinyl)i ndol e, 4-chloro-3- (1-methyl -2-pyr rol i d i nyl ) i ndol e, 5-chloro-3- (1-methyl -2-pyr rol i di nyl )-indole, 5-bromo-3- (1-methyl -2-pyrrol idi nyl ) i ndole, and 5-fl uoro-3- (1-methyl -2-pyr rol i d i nyl ) i ndol e. By use of appro- priate starting indoles in the processes of Youngdale et al., supra, other starting compounds of Formula Ml are readily obta i ned.
The following example is given by way of illustration, it being understood that the 3- (l-methyl -2-pyrrol i d i nyl )-indole can be substituted by any of the 5- (2-pyrrol idinyl)-indoles embraced in Formula III, e.g., those given above.
It is to be understood also that the diethyl malonate can be substituted by other dialkyl malonates, for example, dimethyl, dipropyl , di i sopropyl , dibutyl, diisobutyl, di -sec. butyl , and d i -tert. butyl malonates.
EXAMPLE 1 3-Hydroxymethyl -4- ( i ndol -3-yl )-l-methyl hexahydro- lH-azepine A. Ethyl l-methyl -2-oxo-4- ( i ndol -3- yl )-hexahydro- lH-azepi ne-3-carboxylate A mixture of 3- (l-methyl -2-pyrrol i d i nyl ) i ndol e (50 g. ; 0.25 mole), diethyl malonate (42 g. ; 0.262 mole), powdered sodium hydroxide (1.0 g. ) and xylene (300 ml.) was allowed to reflux under nitrogen for 31.25 hours. During this period ethanol, formed in the reaction, was removed by distillation. Additional 500-mg. portions of powdered sodium hydroxide were added to the reaction mixture after the reaction had proceeded for 7.5 hours and 25.5 hours. The cooled reaction mixture was poured into dilute acetic acid and the mixture was extracted with chloroform. The extract was washed successively with water, dilute ammonium hydroxide, and saturated aqeuous sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The last traces of xylene were removed from the residue by azeotropic distillation, first with toluene and then benzene, A benzene solution of the resulting brown oil was adsorbed on 2 pounds of neutral alumina and chroma tog raphed. With benzene 4.006 g. o of indole, m.p. 51-5 C, was eluted. Elution of the column with 5< ether-chloroform followed by ethyl acetate crystall ization yielded 11.132 g. of ethyl 1-methyl -2-oxo-4- ( i ndol - 3-yl )-hexahydro-lH-azepi ne-3-carboxyl ate (isomer A); m.p. o 191-195 C. A sample of this material was recrysta 11 i zed several times from methanol -ethyl acetate for analysis; m.p. o «. 196.5-198 C. The ultraviolet spectrum (ethanol ) had Λ. max. 220, '281.5, and 290 nu (£ 35,750, 5,950, and 5,150, respectively) with an inflection at 275 nyu (( 5,550). The infrared spectrum (mineral oil) showed NH: 3290 cm."1 and C=0: 1740 and 1627 cm. -1.
Anal . Calcd. for C18H22N203: C, 68.77; H, 7.05; N, 8.9I.
Found: C, 68.36; H, 7.13; N, 8.98.
Concentration of the mother l iquors from the above crystall izations yielded a brown oil (9.09 g. ) which had practically the same infrared spectrum as the above crystall ine product. An ice-cold solution of this material in 150 ml. of absolute methanol was treated with 30 ml. of 0.976 N aqueous sodium hydroxide. The resulting solution was allowed to warm o to about 25 C. After a few hours a crystalline precipitate formed. After 24 hours standing, water was added to the mix- ture which was then concentrated to remove the methanol. The solid which remained was collected by filtration, washed with water, and dissolved in methylene chloride. The methylene chloride solution was washed with water, dried over anhydrous sodium sulfate, and concentrated in vacuo. Crystallization of the residue from methanol -ethyl acetate yielded three crops: 2.888 g., m.p. 209.5-212.5° C ; 0.625 g., m.p. 202.5-205° C. ; o and 0.152 g., m.p. 19 -198 C. An analytical sample of ethyl 1 -methyl -2-oxo-4- ( i ndol -5-yl )-hexahydro-lH-azep i ne-5-carboxy- o late (isomer B), m.p. 212.5-214.5 C., was prepared by re-crystal 1 i z i ng the first crop from methylene chl or i de-methanol . · The ultraviolet spectrum (methanol ) had X_max. 221, 28l, and 290 mj (( 57,100, 6,150, and 5,550, respectively) with an inflection at 27 njo (£ 5,700). The infrared spectrum (chloroform and mineral oil) was almost identical to that of isomer A. A mixed melting point with isomer A was taken; m.p. 201-212.5° C Anal. Calcd. for CieHasNaOa: C, 68.77; H, 7.05; N, 8.91.
Found: C, 68.75; 'H, 7.18; N, 8.92.
B. 5-Hydroxymethyl -4- ( i ndol -5-yl )-l-methyl hexahydro- lH-azepine To a stirred, ice-cold suspension of 5.15 g. of l ithium aluminum hydride in 500 ml. of dry tet rahyd rof uran was added, under nitrogen, 5.0 g. (15.9 mmoles) of the lactam-ester of o Part A (isomer A, m.p. 197-198.5 C). This mixture was allowed to reflux gently for 4.75 hours and stand for 18 hours o at about 25 C. It was then cooled in an ice bath and treated successively with 5 ml. of water, 5 ml. of 15$ aqueous sodium hydroxide, and 15 ml. of water. The inorganic precipitate was collected by f i 1 trat ion and washed with ether. Concentration of the combined filtrate and washing yielded a solid which was dissolved in ethyl acetate, decolorized with acti-vated carbon, and crystall ized to yield 3-hydroxymethyl -4- ( i ndol -3-yl )-l-methyl hexahydro-lH-azepi ne in two crops: 3.07 g., m.p. 143.5-145.5° C, and 0.272 g., m.p. 143.5-145. ° C. o (8o.7# yield). The analytical sample, m.p. 143-145 C. , was prepared by recrystal 1 i zi ng some of this material three times from methanol -ethyl acetate. The ultraviolet spectrum (ethanol ) had max. 223, 282, and 290.5 nyu (£ 34,950, 5, 700, and 5,000, respectively) with an inflection at 276 nyu ( 5,300).
Anal . Calcd. for CieH22N20: C, 7 .38; H, 8.58; N, 10.84.
Found: C, 74.18; H, 8.37; N, 10.53.
Claims (1)
1. r 1825 HAVING HOW particularly described and ascertained he oatoce of our said invention and in what manner the a a me is to be performed, we declare that what we claim is : -1- 1 A member of the group consisting of compounds of the 8 wherein R, R3, and R4 are members of the group consisting of 9 hydrogen and alkyl of not more than 4 carbon atoms, and R2 0 is a member of the group consisting of hydrogen, alkyl of not 1 more than carbon atoms, alkoxy of not more than 4 carbon 2 atoms, and halogen, and the acid addition salts thereof, the 3 N-oxides thereof where R is alkyl and the acid addition salts 4 thereof, and the alkyl quaternary ammonium salts thereof where 5 R i s al kyl . -2- 1 A compound of the following formula: 7 wherein R, R3, and R4 are hydrogen, or alkyl of not more than 8 4 carbon atoms, and R2 is hydrogen, alkyl of not more than 4 9 carbon atoms, alkoxy of not more than 4 carbon atoms, or halo-10 gen. -5- 1 3-Hydroxymethyl -4- ( i ndol -3-yl )-l-methyl hexahydro-lH- 2 azepine. 1825 -4- Process for making compounds of the following formula: wherein R, R3, and R4 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 a dialkyl malonate in the presence of a strong base a compound having the following formula: wherein R, R2, R3, and R4 are as given above to form pound of the following formula: wherein R, R2, R3, and R4 are as given above, and x is alkyl, and reducing the resulting compound with l ithium aluminum hydride. 1825 -5- The process of making compounds of Formula I wherein R, R3, and R4 are hydrogen or alkyl of not more thaw carbon atoms, and R2 is hydrogen, alkyl of not more than 4 carbon atoms, alkoxy of not more than 4 carbon atoms, or halogen, which comprises reducing with lithium aluminum hydride a com-pound of the Formula I I wherein R, Ra, R3, and R4 are as given above, and Rx is alkyl. -6- according to Claims & 5 for The process/ a£ making compounds of Formula II wherein R, R3, and R4 are hydrogen or alkyl of not more than 4 carbon atoms, a is hydrogen, alkyl of not more than 4 carbon atoms, alkoxy of not more than carbon atoms, or halogen, and Rj is alkyl, which comprises reacting dialkyl malonate in the presence of a strong base with a compound of Formula II I wherein R, R2, R3, and R4 are as given above. DATiiD THIS 23rd day of I966* P.O.BOX 1169» Tfilr-AVIV Attorneys fox Applicants
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 |
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IL25766A true IL25766A (en) | 1970-02-19 |
Family
ID=23850471
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
IL25766A IL25766A (en) | 1965-06-22 | 1966-05-13 | 3-hydroxymethyl-4-(indol-3-yl)-hexahydro-1h-azepines and process for their preparation |
Country Status (6)
Country | Link |
---|---|
US (1) | US3364228A (en) |
CH (1) | CH469016A (en) |
DE (1) | DE1620635A1 (en) |
GB (1) | GB1150932A (en) |
IL (1) | IL25766A (en) |
NL (1) | NL6608201A (en) |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3214438A (en) * | 1963-10-14 | 1965-10-26 | Upjohn Co | 3-substituted indoles |
-
1965
- 1965-06-22 US US466101A patent/US3364228A/en not_active Expired - Lifetime
-
1966
- 1966-05-13 IL IL25766A patent/IL25766A/en unknown
- 1966-06-14 GB GB26525/66A patent/GB1150932A/en not_active Expired
- 1966-06-14 NL NL6608201A patent/NL6608201A/xx unknown
- 1966-06-21 DE DE19661620635 patent/DE1620635A1/en active Pending
- 1966-06-22 CH CH901166A patent/CH469016A/en unknown
Also Published As
Publication number | Publication date |
---|---|
CH469016A (en) | 1969-02-28 |
DE1620635A1 (en) | 1970-08-20 |
NL6608201A (en) | 1966-12-23 |
GB1150932A (en) | 1969-05-07 |
US3364228A (en) | 1968-01-16 |
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