GB1586578A - Process for the preparation of 2-(n-(2-hydroxyyethyl)-n-lower alkylaminomethyl) benzhydrols - Google Patents

Process for the preparation of 2-(n-(2-hydroxyyethyl)-n-lower alkylaminomethyl) benzhydrols Download PDF

Info

Publication number
GB1586578A
GB1586578A GB33006/77A GB3300677A GB1586578A GB 1586578 A GB1586578 A GB 1586578A GB 33006/77 A GB33006/77 A GB 33006/77A GB 3300677 A GB3300677 A GB 3300677A GB 1586578 A GB1586578 A GB 1586578A
Authority
GB
United Kingdom
Prior art keywords
process according
compound
methyl
formula
alkanoic acid
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
Application number
GB33006/77A
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.)
Riker Laboratories Inc
Original Assignee
Riker Laboratories Inc
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 Riker Laboratories Inc filed Critical Riker Laboratories Inc
Priority to GB33006/77A priority Critical patent/GB1586578A/en
Priority to DK342278A priority patent/DK149120C/en
Priority to SE7808337A priority patent/SE441826B/en
Priority to NO782643A priority patent/NO146023C/en
Priority to NL787808113A priority patent/NL7808113A/en
Priority to ES472301A priority patent/ES472301A1/en
Priority to CA000308679A priority patent/CA1117551A/en
Priority to NZ188068A priority patent/NZ188068A/en
Priority to IL55286A priority patent/IL55286A/en
Priority to CH830178A priority patent/CH634819A5/en
Priority to IT7826533A priority patent/IT7826533A0/en
Priority to FI782404A priority patent/FI67536C/en
Priority to SU782645753A priority patent/SU984403A3/en
Priority to AU38633/78A priority patent/AU524563B2/en
Priority to DE2834312A priority patent/DE2834312C2/en
Priority to CS785140A priority patent/CS202017B2/en
Priority to MX787290U priority patent/MX5783E/en
Priority to HU78RI681A priority patent/HU175657B/en
Priority to ZA00784437A priority patent/ZA784437B/en
Priority to FR7823129A priority patent/FR2399405A1/en
Priority to BE189728A priority patent/BE869550A/en
Priority to AT569678A priority patent/AT358010B/en
Priority to JP53095155A priority patent/JPS5839145B2/en
Priority to PL1978208868A priority patent/PL111230B1/en
Publication of GB1586578A publication Critical patent/GB1586578A/en
Expired legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
    • C07C215/02—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C215/22—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being unsaturated
    • C07C215/28—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being unsaturated and containing six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D267/00—Heterocyclic compounds containing rings of more than six members having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D267/22—Eight-membered rings

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Steroid Compounds (AREA)

Abstract

2-[N-(2-Hydroxyethyl)-N-lower alkylamino methyl]-benzhydrols of formula <IMAGE> in which R denotes a methyl or ethyl group, X denotes a fluorine, chlorine or bromine atom or a methyl group, Y denotes a fluorine or chlorine atom or a methyl or methoxy group and m and n each denote 0, 1 or 2, are prepared by reducing a compound of formula III in the presence of an alkanoic acid with sodium borohydride in an inert solvent. The benzhydrols of formula I can be directly converted into the corresponding phenylbenz-(f)-2,5-oxazocines, which are valuable physiologically active substances. <IMAGE>

Description

(54) PROCESS FOR THE PREPARATION OF 2-(N-(2-HYDROXYETHYL)-N-LOWER ALKYLAMINOMETHYL) BENZIIYDROLS (71) We, RIKER LABORATORIES, INC., a corporation organised and existing under the laws of the State of Delaware, United States of America, of 19901 Nordhoff Street, Northridge, California 91324, United States of America, do hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement:- The invention relates to a process for the production of 2-[N-(2hydroxyethyl) - N- lower alkylaminomethylbenzhydrols (I). The benzhydrol products of this process can be converted directly to the corresponding phenylbenz(f)-2,5-oxazocines which are valuable physiologically active substances. Thus see United States Patent 3,830,803, United States Patent 3,978,085, British Patent 1,148,717 and Canadian Patent 863,349.
The direct preparation of compounds of type I below from compounds of type II has been known heretofore. This known reaction is carried out by treatment of the starting compound with a metal hydride reducing agent, such as lithium aluminium hydride, in an. inert organic solvent such as tetrahydrofuran or ether (e.g. see British Patent 1,148,717). Reduction with lithium aluminium hydride is not, however, a practical synthetic method for large scale reactions on a commercial basis. The solvents which must be used are fire hazards, lithium aluminium hydride itself is extremely hazardous, and the costs,are prohibitively high.
The present method, on the other hand, can be commercially feasible and advantageous. It uses less hazardous solvents, can be comparatively less expensive and can produce high yields of product of good purity.
This invention provides a process for the preparation of a hydroxyethyl)-N-lower alkylaminomethyl]benzhydrol of the formula:
wherein R is methyl or ethyl, X is fluorine, chlorine bromine or methyl, Y is fluorine, chlorine, methyl or methoxy, and m and n are independently zero, one or two which comprises reducing a compound of the formula
where D is halogen in an inert solvent with sodium borohydride in the presence of an alkanoic acid. Preferably the compound of formula III is obtained by treating a compound of the formula
with a halogenating agent in an inert solvent.
The reduction of certain amides to amines with sodium borohydride in the presence of alkanoic acid has been described in "Sodium Acyloxyborohydride as New Reducing Agents. I. Reduction of Carboxamides to the Corresponding Amines", Tetrahedron Letters No. 10, pages 763-766 and "Reduction of Amides with Sodium Borohydride", Ventron Alembic, Issue No. 9. pages 6 and 7, but this appears to be different from our reduction of the halogenated compound of formula III. Thus the prior described reductions require a large excess of sodium borohydride, with loss of efficiency due to evolution of H2 and probable formation of amine-borane, the reduction allegedly proceeding by way of the alkyloxyborohydride. The reduction of the present invention, on the other hand, proceeds readily in a wide range of solvents with a much smaller excess of sodium borohydride; the presence of the halogen D is essential, the reaction failing in its absence, and in the preferred procedure, in which the formula III compound and alkanoic acid are added gradually to the reaction mixture containing all of the sodium borohydride, there is no evolution of H2 after the first small acid addition.
The product I is ordinarily recovered from the reaction mixture by means of an aqueous workup in solution in the inert solvent. It can be obtained as a pure substance by removal of the solvent by conventional methods or the solution can be used as such, for example in preparing the physiologically active phenylbenz(f)2,5-oxazocines.
The starting materials II of the process of the invention are generally known to the art (see the British and Canadian patents referred to hereinabove). The first (halogenation) step of the process is carried out in an inert solvent, such as a chlorinated hydrocarbon, for example dichloromethane or dichloroethane or an aromatic hydrocarbon such as toluene or benzene. The preferred solvent is dichloroethane. Suitable halogenating agents include phosphorus trichloride, phosphorus tribromide, phosphorus pentachloride and thionyl chloride.
Phosphorus trichloride is presently preferred due to its relatively low cost.
Generally an equivalent amount or a small excess of up to about 10 percent of halogenating agent is used.
The temperature required is moderate, e.g. from 20 to 900C., depending upon the time constraints. At 55 to 800C., the reaction is complete in from about one to about four hours. Excessive reaction temperatures and reaction time should be avoided to minimise the possibility of side reactions. Completion of the reaction is generally monitored chromatographically. Preferably the reaction mixture is cooled, neutralized with aqueous base, then separated and dried.
The reduction reaction can be easily and economically carried out and produce high yields (e.g. from 80 to 100 percent of the theoretical amount). Unlike the prior art process which uses the powerful reducing agent lithium aluminium hydride and difficult and dangerous reaction conditions, the reduction step of the present process can be easily controlled even when carried out on' a large scale; The reaction is carried out in the presence of an alkanoic acid, preferably a lower alkanoic acid containing not more than four carbon atoms such as acetic acid. When the acid is omitted, little or none of the desired product is obtained.
The amount of alkanoic acid used may for example be about 0.1 to about 1.0 mole per mole of sodium borohydride. The reduction is suitably carried out in an inert aliphatic chlorinated hydrocarbon solvent which has a reflux temperature in excess of 60 C., preferably dichloroethane. The reaction temperature is preferably the reflux temperature of the reaction mixture. It can be dangerous to start the reaction below a temperature of 60"C.
The reduction can be carried by adding acetic acid to a mixture of sodium borohydride and the - precursor N-(2-haloethyl)-N-lower alkyl-obenzoylbenzamide (Ill) in ~ dichloroethane. This reaction is normally quite exothermic, although controllable. Alternatively (and preferably for large scale reactions) the reaction is begun on a relatively small scale with all reaction components being present. This initial reaction mixture, which includes the entire amount of sodium borohydride to be used in the larger scale reaction, is maintained at reflux. The balance of the precursor III in dichloroethane together with the balance of the alkanoic acid is added gradually. Using this alternative procedure, less alkanoic acid is necessary (for example less than 0.2 mole per mole of sodium borohydride). In addition, less sodium borohydride may also be used; for example, it is presently preferred to use about 1.5 moles per mole of III compared to 2.0 moles per mole of III when not using the preferred procedure. The reaction can be carried out under an inert (e.g. nitrogen) atmosphere as a safety measure and also to minimize the possibility of side reactions,' although this is generally unnecessary.
After the reduction has proceeded to completion (as conveniently shown by chromatographic analysis), the mixture is added gradually (cautiously at first) to water, then basified and heated at reflux (to destroy any residual sodium borohydride and neutralize the alkanoic acid). The product can then be isolated or alternatively the organic layer containing the product can be separated and used for further reaction to provide the pharmaceutically active phenylbenz(f)2,5-oxazocines.
The following illustrative Examples are provided to show the practice of the process of the invention. Example 2 illustrates just the preparation of a starting compound III.
Example I A complete five-step synthetic sequence beginning with commercially available materials and ending with a pharmaceutically active phenylbenz(f)-2,5oxazocine.
Steps 3 and 4 of this Example illustrate a preferred process of the present invention as part of the sequence.
Step 1-Acid Chloride Preparation.
To a slurry of ortho-benzoylbenzoic acid (222.2 g., 1.0 mole) in dichloroethane (230 ml.) was added in one portion phosphorus trichloride (35.4 ml., 0.46 mole).
After one hour of stirring, the temperature had reached a maximum of 390C.
Stirring at room temperature was continued overnight after which thin layer chromatographic analysis showed complete conversion to the acid chloride. The product layer was separated by decantation.
Step 2-Amide Formation.
To a solution of triethylamine (111.39 g., 1.1 mole) and N-methyl ethanolamine (82.62 g., 1.1 mole) in dichloroethane (400 ml.) was added dropwise the acid chloride-dichloroethane solution of step 1 over one hour at 5 to 120C. after the addition was complete, the reaction mixture was stirred for an additional half hour, by which time thin layer chromatographic analysis showed complete conversion to N-(2-hydroxyethyl)-N-methyl-o-benzoylbenzamide.
Step 3-Preparation of N-(2-chloroethyl)-N-methyl-o-benzoylbenzamide.
To the slurry of product obtained in step 2 at room temperature was added phosphorus trichloride (35.4 ml., 0.406 mole) over five minutes. This caused a 20"C. temperature rise, and the slurry thinned considerably. After warming to 55 to 600 C., and maintaining this temperature for one hour, thin layer chromatographic analysis showed complete conversion to the desired product.
The reaction mixture was cooled to 0 C., and diluted with water (500 ml.) over five minutes maintaining the temperature below 5"C. The two-phase mixture was stirred for five minutes and the layers allowed to separate. The bottom organic layer was washed with an additional 500 ml of water and sufficient base sodium hydroxide) to raise the pH' to about 7 at below 10 C., and the bottom layer was dried over anhydrous sodium sulfate (90 g.).
Step 4--Reduction.
To a slurry of a portion of the solution from step 3 (108 ml.) and sodium borohydride (28.4 g., 0.75 mole) was added dropwise acetic acid (3.5 ml.) After frothing and heat evolution had ceased, the temperature was raised to reflux and maintained for 15 minutes. To this refluxing slurry was added dropwise with stirring over two hours the remainder of the solution of product from step 3 containing 9 ml. of acetic acid. The temperature was maintained at reflux by slight warming of the flask, the addition itself being fairly exothermic. After the completion of addition, the reaction mixture was stirred at reflux for a further hour, at which time thin layer chromatographic analysis showed complete conversion to the desired product. The whole of this procedure was carried out under an atmosphere of nitrogen.
'To the above slurry at room temperature was added dropwise over one hour (very slowly initially) 200 ml. of water. The addition caused fairly heavy effervescence, and the temperature rose to 450C. To the above diluted reaction mixture was added 40 percent aqueous sodium hydroxide (75 ml.). The temperature was raised to reflux and maintained for three quarters of an hour.
The mixture was then cooled and the layers separated to provide a solution of 2 [N-(2-hydroxyethyl)-N-methylaminomethyl]-benzhydrol in dichloroethane.
Step 5-Cyclization.
The benzhydrol from step 4 (still in solution in dichloroethane) was cyclized with aqueous hydrobromic acid using the method of U.S. Patent 3,978,085. The reaction yielded 131.5 g. of 5-methyl-I -phenyl- 1,3 ,4,6-tetrahydro-5H-benz(f)-2,5- oxazocine hydrobromide, m.p. 259-261 0C. The melting point, thin layer chromatographic analysis and infrared spectral analysis all indicate a pure product.
The overall yield of the five steps (beginning with orthobenzoylbenzoic acid) was 6065 percent of theoretical.
Example 2 A mixture of N-(2-hydroxyethyl)-N-methyl-o-benzoylbenzamide (56.66 kg., 200 moles), toluene (10 liters) and phosphorus trichloride (10.07 kg., 10 percent excess) was warmed gently until an exothermic reaction ensued with formation of a hot melt at 770C. after 0.5 hour at 75 to 770 C., thin layer chromatographic analysis indicated complete formation of the N-(2-chloroethyl)-N-methyl-obenzoylbenzamide. Isopropanol (90 liters) was quickly added and the batch rapidly cooled, seeded and chilled to below 0 C. Product was collected, washed with cold isopropanol (2x10 liters) and dried to give 50.6 kg. (83.3 percent) of product, m.p. 85.5-86.20C.
Example 3 A solution of 144 kg. of N-(2-chloroethyl)-N-methyl-o-benzoylbenzamide (481 moles) in 378 kg. of dichloroethane was prepared. A mixture of 50 kg. of this solution, sodium borohydride (273 kg., 721.5 moles, 1.5 equivalents) and dichloroethane (120 liters) at 460C., was treated with acetic acid (0.5 kg,). The temperature rose steadily to reflux at 860C. The remaining dichloroethane solution was added slowly, the exotherm maintaining the mixture at reflux without applied heat during the addition and for two hours after addition was complete.
Thin layer chromatographic analysis was used to check for the completeness of reaction (had the reaction been found to be incomplete, a small further addition of sodium borohydride could then have been made). The complex was then decomposed by cautious slow addition of 100 litres of water at the reflux temperature and then 50 litres of 40% (w/w) aqueous sodium hydroxide solution to form 2-[N-(2-hydroxyethyl)-N-methylaminomethyl]benzhydrol in dichloroethane.
The benzhydrol in dichloroethene was water washed to pH 8 and subsequently cyclized to 5-methyl- 1 -phenyl- 1,3 ,4,6-tetrahydro-5H-benz(f)-2,5-oxazocine as follows: The organic phase was separated and cooled to 200 C.; 48500Xo HBr (224 kg; 149.2 liters) was added with stirring over a half hour period, with cooling to keep the temperature below 50"C. The mixture was gently warmed to reflux, refluxed for 2, hours, cooled to room temperature and then chilled to OOC. The product was collected by centrifuging, spun dry, washed with a total of 110 litres acetone and spun dry again. The damp product was returned to a clean vessel previously charged with toluene (242.8 litres), tap water (110.4 liters) and sodium hydroxide pearl (20.4 kg.), and the mixture stirred and heated to 600 C, stirring being continued four, hour at 600C before standing to separate four, hour. The lower aqueous alkaline layer was run off and the toluene layer washed with 2x 56 litres of tap water at 60 to 700C to pH 7. Toluene was stripped off under reduced pressure and the residual oil cooled to room temperature and then diluted with acetone (220 litres). The solution was clarified by passage via a cartridge filter to a clean vessel. To the stirred, water cooled, clear acetone solution was slowly added hydrochloric acid (38.02 kg; 31.88 litres) over a, I hour period (to pH 1); the resulting slurry was stirred and cooled to room temperature, then chilled to 0 C.
The product was collected by centrifuge, washed well with acteone (total of 110 litres) and sucked dry, then dried in vacuum oven overnight at 5060 C.
Other substituted 2 - [N - (2- hydroxyethyl)- N - lower alkyl aminomethyllbenzhydrols which can be prepared using the process of the present invention as set forth in the preceding Examples, are shown in Table 1.
TABLE I Ex. No. Starting Material Product
TABLE I (Continued) Ex. No. Starting Material Product
WHAT WE CLAIM IS: 1. A process for the preparation of a 2-[N-(2-hydroxyethyl)-N-lower alkylaminomethyl]benzhydrol of the formula:
**WARNING** end of DESC field may overlap start of CLMS **.

Claims (10)

**WARNING** start of CLMS field may overlap end of DESC **. TABLE I (Continued) Ex. No. Starting Material Product WHAT WE CLAIM IS:
1. A process for the preparation of a 2-[N-(2-hydroxyethyl)-N-lower alkylaminomethyl]benzhydrol of the formula:
wherein R is methyl or ethyl, X is fluorine, chlorine, bromine or methyl, Y is fluorine, chlorine, methyl or methoxy, and m and n are independently zero, one or two which comprises reducing a compound of the formula
where D is halogen in an inert solvent with sodium borohydride in the presence of an alkanoic acid.
2. A process according to claim 1 wherein the alkanoic acid is acetic acid.
3. A process according to claim 1 or 2 wherein n and m are zero.
4. A process according to any of claims 1 to 3 wherein the compound of formula III is obtained by treating a compound of the formula
with a halogenating agent in an inert solvent.
5. A process according to any of claims 1 to 4 wherein D is chlorine.
6. A process according to any of claims 1 to 5 wherein the reduction is conducted by mixing the sodium borohydride with a portion of the alkanoic acid and of the formula III compound, and thereafter adding the remaining alkanoic acid and formula III compound gradually to the reaction mixture.
7. A process for the preparation of a 2-[N-(2-hydroxyethyl)-N-lower alkylaminomethyl]benzhydrol, the process being substantially as hereinbefore described in any one of Examples 1 and 3 to 10.
8. A process according to any of claims 1 to 7 wherein the compound of formula III is prepared substantially as hereinbefore described in Example 2.
9. A process according to any of claims 1 to 8 which includes converting the product to a corresponding phenylbenz(f)-2,5-oxazocine.
10. A compound of formula I obtained by a process according to any of claims 1 to 8.
Il. A phenylbenz(f)-2,5-oxazocine obtained by a process according to claim 10.
GB33006/77A 1977-08-05 1977-08-05 Process for the preparation of 2-(n-(2-hydroxyyethyl)-n-lower alkylaminomethyl) benzhydrols Expired GB1586578A (en)

Priority Applications (24)

Application Number Priority Date Filing Date Title
GB33006/77A GB1586578A (en) 1977-08-05 1977-08-05 Process for the preparation of 2-(n-(2-hydroxyyethyl)-n-lower alkylaminomethyl) benzhydrols
DK342278A DK149120C (en) 1977-08-05 1978-08-02 METHOD FOR PREPARING 2- (N- (2-HYDROXYETHYL) -N-ALKYLAMINOMETHYL) BENZHYDROLES
SE7808337A SE441826B (en) 1977-08-05 1978-08-02 SET TO PREPARE A 2 / N- (2-HYDROXYTHYL) -N-LOWER ALKYLAMINOMETHYL / BENZYDROL
NO782643A NO146023C (en) 1977-08-05 1978-08-02 PROCEDURE FOR PREPARING 2- (N- (2-HYDROXYETHYL) -N-LOWER ALKYLAMINOMETHYL) BENZHYDROLES
NL787808113A NL7808113A (en) 1977-08-05 1978-08-02 PROCESS FOR THE PREPARATION OF 2- (N- (2- HYDROXYETHYL) - N-LOWER ALKYLAMINOMETHYL) BENZHYDROLLES.
ES472301A ES472301A1 (en) 1977-08-05 1978-08-02 Process for the preparation of 2-(n-(2-hydroxyyethyl)-n-lower alkylaminomethyl) benzhydrols
CA000308679A CA1117551A (en) 1977-08-05 1978-08-03 Process for the preparation of 2-[n-(2- hydroxyethyl)-n-lower alkylaminomethyl]-benzhydrols
NZ188068A NZ188068A (en) 1977-08-05 1978-08-04 Preparation of 2-(n-(2-hydrocyethyl)-n-loweralkylaminomethyl)-benzhydrol
IL55286A IL55286A (en) 1977-08-05 1978-08-04 Preparation of 2- n-(2-hydroxy-ethyl-)-n-lower alkylamino methyl benzhydrols
CH830178A CH634819A5 (en) 1977-08-05 1978-08-04 Process for the preparation of 2-[N-(2-hydroxyethyl)-N-lower alkyl-amino methyl]-benzhydrols.
IT7826533A IT7826533A0 (en) 1977-08-05 1978-08-04 PROCESS FOR THE PREPARATION OF 2-OPEN PAR. SQUARE N-(2-HYDROXYETHYL)-N-ALKYL(LOWER)AMINOMETHYL CLOSED SQUARE PAR.-BENZHYDROLS.
FI782404A FI67536C (en) 1977-08-05 1978-08-04 PROCEDURE FOR FRAMSTATION OF AV 2- (N- (2-HYDROXETYL) -N-ALKYLAMINOMETHYL) -BENOHYDROLDERIVAT
SU782645753A SU984403A3 (en) 1977-08-05 1978-08-04 Method of producing 2-/n-2(-2-oxyethyl)-n-(lower)-alkylaminomethyl/-benzhydrol
AU38633/78A AU524563B2 (en) 1977-08-05 1978-08-04 Process for the preparation of 2-[n-hydroxyethyl] benzhydrols
DE2834312A DE2834312C2 (en) 1977-08-05 1978-08-04 Process for the preparation of 2[N-(2-hydroxyethyl)-N-lower alkylaminomethyl]-benzhydrols
CS785140A CS202017B2 (en) 1977-08-05 1978-08-04 Process for preparing 1-phenyl-1,3,4,6-tetrahydrobenzoxazocines
MX787290U MX5783E (en) 1977-08-05 1978-08-04 PROCESS FOR THE PREPARATION OF 2- (N- (2-HYDROXYETHYL) -N-LOWER ALKYL-AMINOMETIL) BENZHIDROLES
HU78RI681A HU175657B (en) 1977-08-05 1978-08-04 Process for preparing 2-/n-/2-hydroxyethyl/-n-lower alkylaminomethyl/-benzhydrols
ZA00784437A ZA784437B (en) 1977-08-05 1978-08-04 Process for the preparation of 2-(n-(2-hydroxyethyl)-n-lower alkylaminomethyl)benzhydrols
FR7823129A FR2399405A1 (en) 1977-08-05 1978-08-04 PROCESS FOR THE PREPARATION AND USE OF 2- (N- (2-HYDROXYETHYL) -N-ALKYL LOWER-AMINOMETHYL) BENZHYDROLS
BE189728A BE869550A (en) 1977-08-05 1978-08-04 METHODS FOR THE PREPARATION AND USE OF 2- (N- (2-HYDROXYETHYL) -N-ALKYL LOWER-AMINOMETHYL) BENZHYDROLS
AT569678A AT358010B (en) 1977-08-05 1978-08-04 METHOD FOR PRODUCING 2 (N- (2-HYDROXY-AETHYL) -N-LOWER ALKYLAMINOMETHYL) -BENZHYDROLEN
JP53095155A JPS5839145B2 (en) 1977-08-05 1978-08-04 2↓-[N↓-(2↓-hydroxyethyl)↓-N↓-lower alkylaminomethyl]↓-benzhydrol production method
PL1978208868A PL111230B1 (en) 1977-08-05 1978-08-04 Method of manufacturing lower 2-n-/2-hydroxyethyl/n-alkylaminoethyl-benzhydrols

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
GB33006/77A GB1586578A (en) 1977-08-05 1977-08-05 Process for the preparation of 2-(n-(2-hydroxyyethyl)-n-lower alkylaminomethyl) benzhydrols

Publications (1)

Publication Number Publication Date
GB1586578A true GB1586578A (en) 1981-03-18

Family

ID=10347271

Family Applications (1)

Application Number Title Priority Date Filing Date
GB33006/77A Expired GB1586578A (en) 1977-08-05 1977-08-05 Process for the preparation of 2-(n-(2-hydroxyyethyl)-n-lower alkylaminomethyl) benzhydrols

Country Status (24)

Country Link
JP (1) JPS5839145B2 (en)
AT (1) AT358010B (en)
AU (1) AU524563B2 (en)
BE (1) BE869550A (en)
CA (1) CA1117551A (en)
CH (1) CH634819A5 (en)
CS (1) CS202017B2 (en)
DE (1) DE2834312C2 (en)
DK (1) DK149120C (en)
ES (1) ES472301A1 (en)
FI (1) FI67536C (en)
FR (1) FR2399405A1 (en)
GB (1) GB1586578A (en)
HU (1) HU175657B (en)
IL (1) IL55286A (en)
IT (1) IT7826533A0 (en)
MX (1) MX5783E (en)
NL (1) NL7808113A (en)
NO (1) NO146023C (en)
NZ (1) NZ188068A (en)
PL (1) PL111230B1 (en)
SE (1) SE441826B (en)
SU (1) SU984403A3 (en)
ZA (1) ZA784437B (en)

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FI800076A (en) * 1980-01-11 1981-07-12 Farmos Oy FOERFARANDE FOER FRAMSTAELLNING AV BENZHYDROLDERIVAT
DE3206660A1 (en) * 1982-02-25 1983-09-01 Basf Ag, 6700 Ludwigshafen METHOD FOR PRODUCING O-ACYLAMIDOMETHYLBENZYL HALOGENIDES
JP2006522012A (en) * 2002-12-20 2006-09-28 アラキス リミテッド Benzoxazosin and its use as a monoamine reabsorption inhibitor

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3830803A (en) * 1965-05-10 1974-08-20 Riker Laboratories Inc 5-loweralkyl-1-phenyl-1,3,4,6-tetrahydro-5h-benz(f)-2,5-oxazocines and 4-ones
GB1391862A (en) * 1973-04-04 1975-04-23 Yeda Res & Dev Benzodiazepines

Also Published As

Publication number Publication date
AT358010B (en) 1980-08-11
AU3863378A (en) 1980-02-07
DK149120C (en) 1986-09-08
FR2399405A1 (en) 1979-03-02
CH634819A5 (en) 1983-02-28
HU175657B (en) 1980-09-28
CA1117551A (en) 1982-02-02
SE7808337L (en) 1979-02-06
SE441826B (en) 1985-11-11
DK149120B (en) 1986-02-03
DE2834312A1 (en) 1979-02-15
IT7826533A0 (en) 1978-08-04
IL55286A0 (en) 1978-10-31
PL208868A1 (en) 1979-05-07
JPS5436239A (en) 1979-03-16
ATA569678A (en) 1980-01-15
DK342278A (en) 1979-02-06
MX5783E (en) 1984-07-11
PL111230B1 (en) 1980-08-30
FI67536B (en) 1984-12-31
ES472301A1 (en) 1979-02-16
NO782643L (en) 1979-02-06
NO146023C (en) 1982-07-14
FR2399405B1 (en) 1983-12-09
CS202017B2 (en) 1980-12-31
BE869550A (en) 1979-02-05
NL7808113A (en) 1979-02-07
NZ188068A (en) 1981-03-16
IL55286A (en) 1981-07-31
SU984403A3 (en) 1982-12-23
ZA784437B (en) 1979-07-25
FI67536C (en) 1985-04-10
NO146023B (en) 1982-04-05
FI782404A (en) 1979-02-06
DE2834312C2 (en) 1987-04-09
JPS5839145B2 (en) 1983-08-27
AU524563B2 (en) 1982-09-23

Similar Documents

Publication Publication Date Title
Padwa et al. Synthesis of novel bicyclic nitrogen heterocycles by the intramolecular dipolar cycloaddition reaction of nitrones with allenes and alkynes
NO323980B1 (en) Crystalline dihydrate B or E olanzapine, process for the preparation of Form II olanzapine and preparation
GB1586578A (en) Process for the preparation of 2-(n-(2-hydroxyyethyl)-n-lower alkylaminomethyl) benzhydrols
US4208349A (en) Process for the preparation of 2-[N-(2-hydroxyethyl)-N-lower alkylaminomethyl]benzhydrols
NO167731B (en) PROCEDURE FOR THE PREPARATION OF 4- (3,4-DICHLORPHENYL) -4-PHENYLBUTANIC ACID, AND INTERMEDIATES FOR USE BY THE PROCEDURE.
CA1181073A (en) Process for preparing 4-quinolinones
NZ212652A (en) 3-aminocarbonylmethoxy-5-phenylpyrazoles, pharmaceutical compositions and intermediates
Kano et al. A synthesis of oxazolo [4, 3-a] isoquinoline and related compounds through intramolecular arylation of. alpha.-oxaacyliminium ions
CA1084496A (en) 2-aryl-6-arylidene-1-(substituted aminoalkoxy)-1- cyclohexenes
EP0169602B1 (en) Preparation of n-substituted azetidine 3-carboxylic acid derivatives
KR100525703B1 (en) Preparation of 1-Butyl-4-piperidinylmethylamine
EP0125053B1 (en) Process for preparing secondary amines
JP2000507970A (en) Efficient synthesis of chiral mediators
WO2003007872A2 (en) Process for the preparation of citalopram hydrobromide
EP0294615A1 (en) Cyclobutene-3,4-dione-intermediates and their use in the preparation of histamine h2-antagonists
CA2554125A1 (en) Method for producing a 2-(ethoxymethyl)tropane derivative
KR20030078086A (en) Methods for the preparation of mirtazapine intermediates
NZ207123A (en) Preparation of 8-methoxy-4,8-dimethyl-1-(4-isopropylphenyl)-nonane and -1-nonene
Müller et al. The Synthesis of n, n‐Dimethyl‐2‐(1‐phenyl‐2, 5‐cyclohexadien‐1‐yl)‐ethylamine and of Mesembrine‐Like Metabolites of this Potential Analgesic
NO162461B (en) PROCEDURE TE FOR THE PREPARATION OF AMINE DERIVATIVES.
US4579972A (en) Intermediates for preparing secondary amines
EP0748803B1 (en) Process for producing carboxylic acid derivative
JP2001510830A (en) Method for preparing 1,3-diaza-spiro (4,4) non-1-en-4-one derivative and 1-cyano-1-acylaminocyclopentane intermediate
WO2023122754A1 (en) Processes and intermediates for preparing gb13, gb22 and himgaline
HU192583B (en) Process for preparing 4-quinolines

Legal Events

Date Code Title Description
PS Patent sealed [section 19, patents act 1949]
PE20 Patent expired after termination of 20 years

Effective date: 19980518