Substituted isoxazolidines and isoxazolines as intermediates for

Details Substituted isoxazolidines and isoxazolines as intermediates for Substituted isoxazolidines and isoxazolines as intermediates for

1991-02-19

1992-10-13

Tsang, Cecilia

Organic compounds -- part of the class 532-570 series

Organic compounds

Chalcogen in the nitrogen containing substituent

C07D49804

Patent

active

051552205

DESCRIPTION:

BRIEF SUMMARY
The present invention concerns a new process for the preparation of delmopinol (recINN) as well as new intermediates used in the process. ##STR2##
Delmopinol is a compound which has shown promising results as a plaque inhibitor. It is therefore intended to be used as an ingredient in e.g. mouthrinses and toothpastes. Delmopinol is a morpholino compound which is described in U.S. Pat. No. 4,636,382. This patent also describes several manufacturing methods that can be used for the preparation of this type of morpholino compounds. Up to now delmopinol has been prepared in large scale and in acceptable yields according to a process comprising 16 steps. It is obvious that this manufacturing process is both time and labour consuming. It is therefore an urgent need to provide a manufacturing process that is less time and labour consuming but still gives acceptable yields also in a large scale.
The present invention provides a solution to this problem.


SUMMARY OF THE INVENTION

According to the invention the intermediate isoxazolidines (IV) and isoxazolines (V) and delmopinol, 3-(4-propylheptyl)-4-morpholine-ethanol is prepared by a process comprising the following steps:
a) Preparation of mono- and polyunsaturated 4-propylheptyl compounds I and II, with a terminal olefinic or accty1enibond. unsaturated bonds, or 2-substituted-2-propylpentyl optionally having one or two internal unsaturated bonds, wherein the 2-substituent is a leaving group.
b) Reacting mono- and polyunsaturated 4-propylheptyl compounds (I and II) with morpholine nitrone (III) ##STR3## to produce the compounds IV or V. ##STR4## R is as defined for compounds I and II
c) Reductive ringopening of the compounds IV and V to the compounds VIa, VIb and VIc having the formulas: ##STR5##
d) Tranferring VIb and VIc to the corresponding chloro
analogs.
e) Transferring the compounds of step d) to the compound VIa and
f) Alkylating the compound VIa to 3-(4-propylpentyl)morpholine-ethanol (delmopinol).
The mono- and polyunsaturated 4-propylheptyl compounds I and II are prepared according to examples 1-5.
The leaving group in step a) can be any of usual leaving groups and is suitably selected from hydroxy, alkoxy, acetoxy or tetrahydropyranyloxy.
The morpholine nitrone III, used in step b) can be prepared from N-hydroxylmorpholine by oxidation with e.g. yellow mercuric oxide, palladium and other oxidants, or from the same precursor by photochemical or electrochemical oxidation. It may also be prepared directly from morpholine by oxidation with 2-(phenylsulfonyl)-3-phenyloxaziridine or by catalytic oxidation using hydrogen peroxide and a catalyst, e.g. selenium dioxide or sodium tungstate.
The morpholine nitrone is too unstable to be isolated and is thus used directly for reaction with the unsaturated compounds I and II.
The compounds IV-anti and IV-syn (as racemates) are produced according to examples 6-12 in acceptable yields, and the unreacted starting material is easy to recover and recycle in the process. The compounds formed are diastereomers where IV-anti accounts for 90-98% and IV-syn for 2-10%. The stereochemistry of the adducts is based on analogy. See e.g. C. Hootele et al., Bull.Soc.Chim BeIg., 1987, 96, 57 and references cited therein. The stereochemistry of compounds IV, as well as the degree of unsaturation, is not of importance in view of the total synthesis. All compounds IV converge to the same final product through the following steps.
Step c) can be carried out by treatment of compound IV and V, preferably with an acid e.g. p-toluenesulfonic acid, in a lower alkohol, preferably isopropanol, in a reductive milieu. This consists of a catalyst, preferably Pd-C, under H.sub.2 -pressure, preferably 3-7 atm.
Step d) is performed by reacting the reaction mixture from step c) with a chlorinating agent, preferably by boiling with thionyl chloride.
In step e) the compounds from step d) are dechlorinated by hydrogenation, preferably with Raney-Ni as catalyst.
In step f) finally, the compound VIa is alkylated, preferably by treatment with chloroethanol

REFERENCES:
patent: 4596874 (1986-06-01), Murahashi et al.

Affiliated with

Also associated with

Rating

Substituted isoxazolidines and isoxazolines as intermediates for does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Substituted isoxazolidines and isoxazolines as intermediates for, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Substituted isoxazolidines and isoxazolines as intermediates for will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-1301698