GB1582240A - Creation of Inventions and Patents with Artificial Intelligence

GB1582240A – Process for preparing 2-halo-(benzodioxan-2-yl) ethanol derivatives
– Google Patents

GB1582240A – Process for preparing 2-halo-(benzodioxan-2-yl) ethanol derivatives
– Google Patents
Process for preparing 2-halo-(benzodioxan-2-yl) ethanol derivatives

Download PDF
Info

Publication number
GB1582240A

GB1582240A
GB2137579A
GB2137579A
GB1582240A
GB 1582240 A
GB1582240 A
GB 1582240A
GB 2137579 A
GB2137579 A
GB 2137579A
GB 2137579 A
GB2137579 A
GB 2137579A
GB 1582240 A
GB1582240 A
GB 1582240A
Authority
GB
United Kingdom
Prior art keywords
erythro
formula
benzodioxan
dried
washed
Prior art date
1977-12-06
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
GB2137579A
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.)

John Wyeth and Brother Ltd

Original Assignee
John Wyeth and Brother Ltd
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.)
1977-12-06
Filing date
1977-12-06
Publication date
1981-01-07

1977-12-06
Application filed by John Wyeth and Brother Ltd
filed
Critical
John Wyeth and Brother Ltd

1977-12-06
Priority to GB2137579A
priority
Critical
patent/GB1582240A/en

1981-01-07
Publication of GB1582240A
publication
Critical
patent/GB1582240A/en

Status
Expired
legal-status
Critical
Current

Links

Espacenet

Global Dossier

Discuss

Classifications

C—CHEMISTRY; METALLURGY

C07—ORGANIC CHEMISTRY

C07D—HETEROCYCLIC COMPOUNDS

C07D319/00—Heterocyclic compounds containing six-membered rings having two oxygen atoms as the only ring hetero atoms

C07D319/10—1,4-Dioxanes; Hydrogenated 1,4-dioxanes

C07D319/14—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems

C07D319/16—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems condensed with one six-membered ring

C07D319/20—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems condensed with one six-membered ring with substituents attached to the hetero ring

Description

(54) PROCESS FOR PREPARING 2-HALO-[BENZODIOXAN-2-YL]ETHANOL
DERIVATIVES
(71) We, JOHN WYETH & BROTHER LIMITED a British Company of Huntercombe Lane South, Taplow, Maidenhead, Berkshire, SL6 OPH, 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:
This invention relates to a process for preparing ethanol derivatives useful as chemical intermediates.
In our copending cognate UK Patent Applications Nos. 51781/76 and 45142/77 (Serial
No. 1582239) there are described and claimed compounds of formula
wherein X represents oxygen or sulphur; Y represents -CHOH- or

Z represents
or a direct bond;
R represents cycloalkyl having 5 to 7 ring carbon atoms or an optionally substituted aryl, or heteroaryl radical, or when Z is a direct bond R can also represent hydrogen; R1 represents hydrogen or lower alkyl; R2 represents hydrogen, halogen, lower alkyl or lower alkoxy, R3 represents lower alkyl or hydrogen; and and ss each represent hydrogen or together represent a direct bond between the carbon atoms to which they are attached and acid addition and quaternary ammonium salts thereof.
The term “lower” as used herein in connection with a group or molecule means the group or molecule contains 1 to 6 carbon atoms.
Compounds of formula I, wherein Y is CHOH and cc and (3are a direct bond, having the erythro configuration of asymmetric centres are particularly preferred, being active in reducing heart rate. Such erythro compounds of formula I may be prepared by reacting compounds of formula
having the erythro configuration, where R’ and R2 are as hereinbefore defined with compounds of formula
R-Z-N=C=X (Ill) wherein X, R and Z are as defined in connection with formula I, R being other than hydrogen. Usually the reaction to form the compound of formula I takes place at room temperature.
Erythro compounds of formula II may themselves be prepared by reacting an appropriate erythro 2-halo-1-[1,4-benzo-dioxan-2-yl]ethanol with 4-benzamidopiperidine, hydrolysing the product to remove the benzoyl group to give erythro 4-aminopiperidine derivatives of formula II: which compounds may be alkylated to give 4-loweralkylamino derivatives.
We have now surprisingly found a route for the preparation of the 2-halo-1-[1,4benzodioxan-2-yl-]ethanol derivatives which provides the erythro form in excess of the threo form.
Accordingly, this invention provides a method for preparing an erythro-2-halo-1-[1,4 benzodioxan-2-yl]ethanol having the formula
OH R2- f CH-CH2ho109en (i\) in excess of the threo form, which comprises reducing a ketone of formula
C.
2 f C-CH2 hologen O (V) in which formulae R2 is as hereinbefore defined, with an alkali metal borohydride at a temperature at or below -20 C, e.g. from -20 to -100 , preferably from -50″ to -90 , most preferably about -70 C.
This reaction may be carried out in the presence of an alkanol having 1 to 3 carbon atoms, e.g. methanol. When reduction is carried out at about -70 C the erythro isomer can be produced substantially in excess of the threo isomer. For example reduction at -700C in methanol gave a 7:3 ratio of erythro to threo isomer.
The erythro compounds of formula IV may also be used directly in a process for preparing erythro compounds of formula I wherein X represents oxygen, and R is other than hydrogen. Such a process comprises reacting an erythro compound of formula IV with a compound of formula
wherein X, Z, R and Rl are as defined above in connection with formula I; being other than hydrogen. Such a reaction is conveniently carried out.in the presence of base, e.g. an alkali metal carbonate such as potassium carbonate or a lower alkyl amine, e.g. triethylamine, in a suitable inert solvent, e.g. dimethylformamide, dichloromethane, isopropanol.
The following Example 1 illustrates the invention; Example 2 illustrates the use of the intermediate.
EXAMPLE 1 Erythro-1 – (1, 4-Benzod ioxan-2-yl-) -2-bromoethanol 2-Bromoacetyl-1,4-benzodioxan(53.8g) in methanol (500 ml) was cooled to -70 C.
Sodium borohydride (10.3g) was added and the solution stirred at -700C for 12 hours. The solution was treated with hydrobromic acid until acidic and the solvent evaporated. The residue was dissolved in ether and the ether extracts were washed with sodium bicarbonate solution; then water and dried (MgSO4) and evaporated to give a white solid. This was recrystallised eight times from petroleum spirit 60-80 to give 14 grams of the title compound.
EXAMPLE 2 Erythm-4-benzarnido-1 (1, 4-benzodioxan ioxan-2-yl-) -2-hydrnxyethyI}pipeiidine (a) Erythro l-(1,4-benzodioxan-2-yl-)-2-bromoethanol (7.()3g 0.031 m),4benzamidopiperidine (5.59g 0.027m) and triethylamine (4g 0.04m) were refluxed in ethanol (250mls) for 24 hours. The solvent was evaporated and the residue dissolved in chloroform and the chloroform extract washed with water, dried (MgSO4) and evaporated to give a white solid (7.95g 65%). This solid (1.5g) was dissolved in the least amount of methanol and acidified with ethanolic HC1. The title compound crystallised, was filtered off and dried (1.04g)
Melting Pt. 246-249″C Microanalysis: C22H”N204.HCl requires C, 63.08%; H, 6.50%; N, 6.69%;
Found: C, 62.99%; H, 6.55%; N, 6.39%
(b) Erythro 4-amino-1-[2- (1, 4-óenzod ioxan-2-yl-)-2-hyd roxyethyll iperid ine Erythro-4-benzamido l -[2-( l,4-benzodioxan-2-yl-)-2-hydroxyethyl fpiperidine (t4 .23g) prepared according to Example 3(b) was suspended in 6 N hydrochloric acid (250 mls) and boiled under reflux for 8 hours. The solid was filtered off and washed with water. The aqueous filtrate and washings were treated wtih anhydrous potassium carbonate powder until basic and these extracted with chloroform. The combined chloroform extracts were washed with water, dried (MgSO4), and evaporated to give title compound (10.4 g 1(10%).
WHAT WE CLAIM IS:
1. A process for preparing an erythro 2-halo-1-[1,4-benzodioxan-2-yl-]ethanol having the formula
OH 2 CH-CH2hologen O (1V) in excess of the threo isomer, wherein R2 is hydrogen, halogen, lower alkyl or lower alkoxy which comprises reducing at a temperature at or below -20″C, a corresponding compound of formula
0 R24 f C-CHi holc9en with an alkali metal borohydride, in an alkanol solvent having 1 to 3 carbon atoms.
2. A process as claimed in Claim l where halogen is bromine.
3. A process as claimed in Claim 1 or Claim 2 in which solvent is methanol.
4. A process as claimed in any one of Claims l to 3 which is effected at a temperature from -20 C to -100″C.
5. A process as claimed in any one of Claims 1 to 3 which is effected at a temperature about -70″;.
6. A process as claimed in Claim I substantially as hereinbefore described with reference to Example l.
7. A compound of formula IV as defined in Claim l whenever prepared by a process as claimed in Claims l to 6.
**WARNING** end of DESC field may overlap start of CLMS **.

Claims (7)

**WARNING** start of CLMS field may overlap end of DESC **. and the chloroform extract washed with water, dried (MgSO4) and evaporated to give a white solid (7.95g 65%). This solid (1.5g) was dissolved in the least amount of methanol and acidified with ethanolic HC1. The title compound crystallised, was filtered off and dried (1.04g) Melting Pt. 246-249″C Microanalysis: C22H”N204.HCl requires C, 63.08%; H, 6.50%; N, 6.69%; Found: C, 62.99%; H, 6.55%; N, 6.39% (b) Erythro 4-amino-1-[2- (1, 4-óenzod ioxan-2-yl-)-2-hyd roxyethyll iperid ine Erythro-4-benzamido l -[2-( l,4-benzodioxan-2-yl-)-2-hydroxyethyl fpiperidine (t4 .23g) prepared according to Example 3(b) was suspended in 6 N hydrochloric acid (250 mls) and boiled under reflux for 8 hours. The solid was filtered off and washed with water. The aqueous filtrate and washings were treated wtih anhydrous potassium carbonate powder until basic and these extracted with chloroform. The combined chloroform extracts were washed with water, dried (MgSO4), and evaporated to give title compound (10.4 g 1(10%). WHAT WE CLAIM IS:

1. A process for preparing an erythro 2-halo-1-[1,4-benzodioxan-2-yl-]ethanol having the formula
OH 2 CH-CH2hologen O (1V) in excess of the threo isomer, wherein R2 is hydrogen, halogen, lower alkyl or lower alkoxy which comprises reducing at a temperature at or below -20″C, a corresponding compound of formula
0 R24 f C-CHi holc9en with an alkali metal borohydride, in an alkanol solvent having 1 to 3 carbon atoms.

2. A process as claimed in Claim l where halogen is bromine.

3. A process as claimed in Claim 1 or Claim 2 in which solvent is methanol.

4. A process as claimed in any one of Claims l to 3 which is effected at a temperature from -20 C to -100″C.

5. A process as claimed in any one of Claims 1 to 3 which is effected at a temperature about -70″;.

6. A process as claimed in Claim I substantially as hereinbefore described with reference to Example l.

7. A compound of formula IV as defined in Claim l whenever prepared by a process as claimed in Claims l to 6.

GB2137579A
1977-12-06
1977-12-06
Process for preparing 2-halo-(benzodioxan-2-yl) ethanol derivatives

Expired

GB1582240A
(en)

Priority Applications (1)

Application Number
Priority Date
Filing Date
Title

GB2137579A

GB1582240A
(en)

1977-12-06
1977-12-06
Process for preparing 2-halo-(benzodioxan-2-yl) ethanol derivatives

Applications Claiming Priority (1)

Application Number
Priority Date
Filing Date
Title

GB2137579A

GB1582240A
(en)

1977-12-06
1977-12-06
Process for preparing 2-halo-(benzodioxan-2-yl) ethanol derivatives

Publications (1)

Publication Number
Publication Date

GB1582240A
true

GB1582240A
(en)

1981-01-07

Family
ID=10161868
Family Applications (1)

Application Number
Title
Priority Date
Filing Date

GB2137579A
Expired

GB1582240A
(en)

1977-12-06
1977-12-06
Process for preparing 2-halo-(benzodioxan-2-yl) ethanol derivatives

Country Status (1)

Country
Link

GB
(1)

GB1582240A
(en)

Cited By (1)

* Cited by examiner, † Cited by third party

Publication number
Priority date
Publication date
Assignee
Title

EP0367888A1
(en)

1988-11-08
1990-05-16
ISTITUTO LUSO FARMACO D’ITALIA S.p.A.
2,2-Disubstituted 2,3-dihydro-1,4-benzodioxin derivatives having hypotensive activity

1977

1977-12-06
GB
GB2137579A
patent/GB1582240A/en
not_active
Expired

Cited By (1)

* Cited by examiner, † Cited by third party

Publication number
Priority date
Publication date
Assignee
Title

EP0367888A1
(en)

1988-11-08
1990-05-16
ISTITUTO LUSO FARMACO D’ITALIA S.p.A.
2,2-Disubstituted 2,3-dihydro-1,4-benzodioxin derivatives having hypotensive activity

Contact information