LT3370B - Method for the preparation of delmopinol and intermediates for the said method - Google Patents

Abstract

The new 3-(4-propylheptyl)-morpholine-ethanol (delmopinol) extraction method is described, using the intermediates, which have the formula:<IMAGE>where R - 2-propylpentyl, in which there can be one, two or three inner non-saturated compounds, or 2-changed-2-propylpentyl, in which there can be one or two non-saturated compounds and in which the substitute in a 2 position is a small group.

Description

Delmopinol is a compound that has shown promising results as a stain inhibitor. It can therefore be used as a component in mouthwash or toothpastes. Delmopinol is a morpholine derivative described in U.S. Pat. 4636382. This patent also describes some industrial methods that can be used to make this type of morpholine compounds. To date, large amounts of delmopinol with acceptable yields have been produced by a process consisting of 16 steps. It goes without saying that such an industrial process requires considerable time and effort. Therefore, the need to develop an industrial process that requires less time and effort and to produce large quantities of the compound with acceptable yields has matured.

The present invention provides a solution to such a problem.

According to the present invention, intermediate isoxazolidines (IV) and isoxazolines (V), as well as delmopinol, 3- (4-propylheptyl) -4-morpholine-ethanol, are obtained by a process comprising the following steps:

(a) 4-Propylheptyl mono- and polyunsaturated I and II having an ethylene or acetylene end-bond

I: CH ₂ = CH-R

II: CH = CR where R is 2-propylpentyl which may have one, two or three internal unsaturated bonds or 2-substituted-2-propylpentyl which may have one or two unsaturated bonds and which is substituted in the 2-position by a leaving group , receiving;

(b) Reaction of 4-propylheptyl mono- and polyunsaturated compounds (I and II) with morpholine nitrone (III)

wherein R is the same as in compounds I and II; 15th

(c) Reductive IV and V of compounds ring opening, in the formation of compounds VI a, VI b and VI c, of which formulas: wow k; 1 H H 1 H

6th century

VI b

VI c

d) conversion of VI b and VI c to the corresponding chlorine analogs;

e) converting the compounds obtained in step d into compound VIa; and

f) alkylation of compound VIa to 3- (4-propylpentyl) morpholinoethanol (delmopinol).

The 4-propylheptyl mono- and poly-unsaturated compounds are prepared according to the procedures described in Examples 1-5.

The leaving group in step a may be any one of the conventional leaving groups, and is usually selected from hydroxy, alkoxyl, acetoxyl or tetrahydropyralinoxyl.

The morpholine nitron III used in step (b) may be obtained by oxidation of N-hydroxymorpholine, for example, with yellow mercury oxide, palladium or other oxidants, or by photochemical or electrochemical oxidation of the same starting material. It can also be obtained from morpholine by oxidation with 2- (phenylsulfonyl) -3-phenyloxaziridine or by catalytic oxidation using hydrogen peroxide and a catalyst such as selenium dioxide or sodium tungstate.

Morpholine nitron is not stable enough to be isolated and used directly for reaction with unsaturated compounds I and II.

IV-anti and IV-sin (racemate) compounds are obtained according to

Examples 6-12 provide satisfactory yields, and unreacted starting compounds can be readily isolated and re-reacted. The resulting compounds are diastereomers in the ratio of 90-98%

IV-anti and 2-10% IV-sin. Stereochemistry of adducts has been determined by analogy (see, e.g., C. Hootele et al., Bull.Soc.Chim.Belg. 1987, 96, 57 and references cited herein). The stereochemistry of Compound IV, as well as the degree of unsaturation, are not determinants of synthesis. Going through the next steps, all IV compounds give the same end product.

Step C can be carried out by treating compounds IV and V with the best acid such as para-toluene sulfuric acid, using a lower alcohol such as (preferably) isopropanol as solvent, under reducing conditions.

Hydrogen (preferably 3-7 atmospheric pressure) and a catalyst, preferably Pd-C, are used for the reduction.

Step D is carried out by treating the reaction mixture of step c with a chlorinating agent; preferably boiled with thionyl chloride.

In step E, the compounds obtained in step d are dechlorinated by hydrogenation; Renee nickel is best used as a catalyst.

In step F, the compound IVa is alkylated, preferably with chloroethanol and potassium iodide, with the addition of potassium hydroxide from time to time; the desired 3- (4-propylheptyl) -4-morpholine-ethanol is formed.

As stated in the application, the most important aspect of the present invention is the preparation of intermediates IV and V since they are the most important intermediates for the preparation of delmopinol.

The invention is further illustrated by the Examples wherein Examples 1-5 describe the preparation of the final alkenes / alkynes. Examples 6-12 describe the preparation of isoxazolidines (IV) and isoxazolines (V), and Examples 13-15 describe the preparation of the final product, delmopinol.

Examples Example

Preparation of 4-propyl-l-heptene (Ia)

Dissolve 100 g of 4-propylheptyl bromide in 400 ml of benzene and add gradually 90 g of tert-BuOK in 300 ml of dimethylsulfoxide. The temperature is maintained below 50 ° C. The mixture is stirred for 2 hours, after which 600 ml of water is added. The organic layer was separated and the aqueous layer was extracted with petroleum ether (boiling point 40-60 ° C). The organic phases are combined and washed with water and brine. Dry over Na ₂ SO ₄ , evaporate the solvent and distill.

Yield: 23.2 g (boiling point 56-59 ° C / 75 torr). 'ή-ΒΜΒ. (CDCl ₃ ): δ, 1.09 (6H, CH ₃ ), 1.2 (9H, CH ₂ CH), 2.0 (2H,

CH ₂ C = C), 4.8-5.1 (2H, CH ₂ = C), 5.5-6.0 (1H, CH = C).

example

Preparation of 4-propyl-1,3-heptadiene (Ib) and cis / trans-4-propyl-1,4-heptadiene (Ic)

To a solution of 80 g PBr ₃ in 250 ml of dry diethyl ether is slowly added 4-hydroxy-4-propyl-1-heptene at -30 to -20 ° C. The temperature is then maintained at 25 - 10 ° C for 2 hours and at -5 ° C for 15 hours. The reaction mixture was poured onto ice (500 g) and diethyl ether (500 mL) was added. The ether layer was separated, washed with NaHCO ₃ solution ( ₂ x 250 mL), dried over MgSO ₄ and evaporated. The residue (60.0 g) was added to a solution of 1,8-diaza-bicyclo [4,5,4] undec-7-ene (94 g) in benzene (250 ml) and heated under reflux for 2 hours. After cooling, 1000 ml of diethyl ether are added and the ether layer is washed with 5M HCl (2 x 300 ml) and water (3 x 250 ml). It was dried over MgSO ₄ and the solvent was evaporated. The residue (38.2 g) is distilled to give 30.6 g of a fraction boiling at 48-56 ° C / 8 tor. Gas chromatography was found to contain 47% cis / trans-4-propyl-1,4-heptadiene (undissolved) and 46% 4-propyl-1,3-heptadiene,

The 1,4- and 1,3-isomers were separated by preparative gas liquid chromatography (Perkin Elmer F 21) using a 12 m x 8 mm column with 20% carbovax 20M at 180 ° C and a nitrogen pressure of 1.9 atm.

¹ H-NMR (CDCl ₃ ):

lb: δ, 0.9 (6H, ch ₃ ), 1.3-1.5 (4H, CH ₂ OC = C), 1.9-2.2 (4H, CH ₂ C = C) 4.9-5.1 (2H, CH ₂ = C), 5.8-5. 9 (1H, C = CHO-C), 6, 5-6, 7 (1H, C = CCH = C) Ic: δ, 0.8-0.9 (6H, CH ₃ ), 1.3-1.5 (2H, CH ₂ CC = C) 1.9-2.1 (4H, CH ₂ C = C), 2.6-2.8 (2H, C = CCH ₂ C = C) 4.9-5.1 (2H, CH ₂ = C), 5.1-5.3 (1H, CH = C), 5.6-5.9 (1H, CH = C).

example

Preparation of 4-hydroxy-4-propyl-1-heptene (1 d)

A solution of 113 g of 4-heptanol in 1000 ml of dry diethyl ether is slowly added dropwise to a solution of 38.5 g of Mg and 178 g of allyl bromide in 500 ml of dry diethyl ether. The mixture was then refluxed for 10 hours. The reaction mixture is poured into 150 g of ice, 450 ml of a mixture of 20% NH ₄ Cl and 350 ml of 5 M HCl. The ether layer was separated and the aqueous layer was extracted with diethyl ether (3 x 300 mL). The organic phases are combined, washed with Na ₂ CO ₃ solution and water, dried over Na ₂ SO ₄ and evaporated with ether. The residue is redistilled. Yield: 142 g (boiling point 38-40 ° C / 0.1 L toro).

¹ H-NMR (CDCl ₃ ): δ, 0.9 (6H, CH ₃ ), 1.3-1.6 (9H, CH ₂ OH),

2.1-2.3 (CH ₂ C = C) 5.0 to 5.2 (CH ₂ = C)

5.6-6.1 (CH = C).

example

Preparation of 2-propylpentyl tosylate

To a mixture of 52 g of 2-propylpentanol and 86 g of paratoluene sulfuric acid was added 48 g of pyridine in 175 ml of chloroform at 0-3 ° C and under a nitrogen atmosphere. The mixture is kept for 30 minutes. At 0 ° C and then at room temperature for 19 hours. The reaction mixture was cooled and 3M HCl (300 mL) was added. The organic layer is separated and washed with water and brine. Dry over Na ₂ SO ₄ , evaporate to give 110 g of 2-propylpentyltyl tosylate.

¹ H-NMR (CDCl ₃ ): δ, 0.8 (6H, CH ₃ ), 1.1-1.8 (9H, CH ₂ , CH), 2.4 (3H, ArCH ₃ ), 3.9 (2H, OCH ₂ ),

7.2-7.9 (4H, ArH).

example

Preparation of 4-propyl-l-heptin (Ha)

Place 18.4 g of lithium acetylenide complex with ethylenediamine in a flask filled with argon. Dimethyl sulfoxide (100 mL) was added and the mixture was cooled to 15 ° C. 50 g of 2-propylpentyl-para-toluenesulfonate are slowly added. Stir the mixture at room temperature for 1 hour, then add 50 ml of water (keeping the temperature below 35 ° C) with vigorous stirring. The mixture was poured into 600 mL water and extracted with hexane (3x100 mL). The combined hexane extracts were washed with brine and dried over Na ₂ SO ₄ . The hexane is evaporated off and the residue is distilled under vacuum. Yield: 13.1 g (boiling point 75-80 ° C / 85 torus).

¹ H-NMR (CDCl ₃ ): δ, 0.9 (6H, CH ₃ ), 1.3 (9H, CH ₂ , CH), 1.9 (1H, CH = C), 2.2 (2H, CH ₂ C = C).

example

General procedure for the preparation of isoxazolidines (IV) and isoxazoline (V) (method Ά)

35% H ₂ O ₂ (43 g) was added to a mixture of alkenes / alkynes with unsaturated terminal groups (10 g), morpholine (19 g) and Na ₂ WO ₄ , H ₂ O (2.7 g) in methanol (50 g). at such a rate that the boiling point is 50-60 ° C. Ethanol (100 mL) was added to the mixture heated at 50-60 ° C for 18 hours. Most methanol / ethanol was evaporated in vacuo, water (300 mL) was added and the mixture was extracted with diethyl ether (4 x 50 mL). The organic layer is washed with water and brine. Na ₂ SO _{4 is} dried, evaporated to give isoxazolidines (IV) / isoxazoline (V). (Other combinations of solvents such as CHC1 ₃ , toluene and CH ₃ CC1 _{3 may also be used} ).

example

Preparation of isoxazolidine (IVd) (Method A) g 35% H ₂ O _{2 was} added to 31 g of morpholine, 120 ml of methanol, 125 ml of ethanol, 19 g of 4-hydroxy-4-propyl-heptene and 4.8 g of Na ₂ WO _4. . 2 H ₂ O mixture at a rate such that the boiling point is maintained at 50-60 ° C. An additional 200 ml of ethanol is added and the mixture is kept at 50-60 ° C for 18 hours. Most of the methanol / ethanol was evaporated in a good vacuum, then 600 mL of water was added and the mixture was extracted with ether (4 x 200 mL). The ether layer was washed with 5 M HCl (4 x 100 mL) to give 13.5 g of starting material. The acid layer is basified and extracted with ether. Dry over Na ₂ SO ₄ and evaporate the ether. 5.9 g of IVd (90% anti-10% sin) are obtained.

example

Preparation of isoxazolidine IVd (method B)

To a cooled mixture of 330 g of morpholine and 52 g of Na ₂ WO ₄ .2H ₂ O is slowly added 735 g of 30% H ₂ O _{2 in} 400 mL of water. The temperature of the reaction mixture is maintained below 20 ° C. Half a portion of the resulting nitrone mixture was then added to 100 g of 4-hydroxy-4-propyl-1-heptene in refluxing 900 ml of methanol. Boil for another 2.5 hours, add another half of the nitron mixture to this boiling mixture and boil for another 2.5 hours. with reflux. The mixture was cooled and extracted with toluene (750 mL). The toluene layer was extracted with 5 M HCl (650 mL). 57 g of the starting material, 4-hydroxy-4-propyl-1-heptene, were isolated from the organic phase. The aqueous phase was basified with 5 M NaOH to pH 8.8 and extracted with toluene (500 mL). Na ₂ SO _{4 is} dried and the solvent is evaporated to give 37 g of IVd (a mixture of syn-anti stereomers).

Examples 9-12

Examples 9-12 are used to validate the processes described in Example 6. They are presented in Table 1.

in example Va the product was not isolated. Its yield was determined by ¹ H-NMR (CDCl ₃ ): δ, 0.9 (6H, CH ₃ ), 1.3 (9H, CH ₂ CH), 4.5 (1H, CH = C). This product was used as an intermediate for further work;

no formation of by-products was observed.

table

Product

For example, Unsaturated compound

Yield ¹¹ Sin / anti (%) ratio ² '

3:97

10:90

The yields are not optimized.

The stereochemistry of the adduct was determined by analogy (see, e.g., C. Hootele et al., Bull.Soc.Chim.Belg. 1987, 96, 57 and references cited herein).

Compound IVc is a mixture of eis and trans isomers (50:50); the syn-anti ratio of each isomer is about 3:97.

example

Reductive ring opening of isoxazolidine IVd

A mixture of 10 g of toluene sulfuric acid isopropanol was shaken at room temperature for 15 hours with hydrogen pressure of isoxazolidine IVd, 27 g of parair, and 1.5 g of 10% Pd-C in 100 ml of glass for 70-80 ° C for 3 to 7 atmospheres. The reaction mixture was then cooled, filtered and the isopropanol evaporated in a good vacuum. An excess of 5 M NaOH was added and the mixture was extracted with diethyl ether. After drying and evaporation of the solvent, 8.8 g of a mixture of compounds VIa, VIb and VIc (R = 2-propylpentyl) are obtained.

example

Chlorination of the hydroxyalkylmorpholines VIb and VIc (R = 2-propylpentyl) and dechlorination of the resulting compounds are added to 5 g of a mixture of VIa, VIb and VIc (R = 2-propylpentyl) dissolved in 7 ml of chloroform. The mixture is stirred for 3 hours. 20 ° C and heated for 1 hour. with reflux. After evaporation of the solvent, 5 M NaOH (25 mL) was added and the mixture was extracted with diethyl ether (3 x 15 mL). The ethereal extracts are combined and washed with water and brine. After drying and evaporation of the solvent, 4.8 g of chloro analogs and VIa are obtained.

This mixture is hydrogenated for 24 hours with the addition of 5 g of Renee nickel catalyst, 5 g of triethylamine and 250 ml of dioxane. At 100 ° C under 120 atmospheric hydrogen pressure. The reaction mixture was filtered through zeolite and evaporated. 30 mL of 5 M NaOH was added and the mixture was extracted with diethyl ether (3x15 mL). After drying and evaporation of the solvent, 4.3 g of pure 3- (4-propylheptyl) morpholine are isolated.

example

Preparation of 3- (4-propylheptyl) -4-morpholine-ethanol

A mixture of 2.5 g of 3- (4-propylheptyl) morpholine, 3.5 g of chloroethanol, 1.1 g of potassium iodide and 7 ml of ethanol is heated under reflux for 5 hours. Then 0.3 g KOH solution in 1.5 ml ethanol was added and refluxed for 2 hours and 0.2 g KOH solution in 1.0 ml ethanol was again added. After refluxing for another 7 hours, a third portion of 0.1 g KOH in 0.5 ml ethanol was added. After boiling for a further 2 hours, the solvent is evaporated and 10 ml of water are added. The mixture is extracted with diethyl ether (3 x 10 mL), the organic phases are combined and washed with water and brine. After drying and evaporation of the solvent, 2.5 g of 3- (4-propylheptyl) -4-morpholine-ethanol are isolated.

DEFINITION OF INVENTION

Claims (8)

DEFINITION OF INVENTION A process for the preparation of 3- (4-propylheptyl) -morpholine-ethanol (delmopinol), characterized in that 5 performs the following reactions: (a) 4-propylheptyl mono- and polyunsaturated compounds of formula I or II: CH ₂ = CH-R (I) CH = C-R (II) wherein R is 2-propylpentyl which may have one, two or three internal unsaturated bonds or 2-substituted-2-propylpentyl which may have one or two internal unsaturated bonds and the substituent at 2 At position 15 is a leaving group; b) Reaction of 4-propylheptyl mono- and polyunsaturated compounds (I and II) with morpholine nitrone (III) I 0 ' III which yields compounds IV or V 0,, 0 IV anti IV-syn wherein R is as defined above; (c) reductive ring opening of compounds IV and V to form compounds VIa, VIb, and VIc, of the formula: VIa VIb VIc, (d) conversion of VIb and VIc to the corresponding chlorinated derivatives; e) converting the compounds obtained in step d into compound VIa; and f) alkylation of compound VIa to form delmopinol (3- (4-propylheptyl) morpholine-ethanol). 2. A process according to claim 1, wherein the leaving groups are selected from hydroxyl, alkoxyl, acetoxyl or tetrahydropyranyloxy. 3. A process according to claim 1 wherein the unsaturated compound has the formula I wherein R is 2-propylpentyl, 2-propyl-1-pentenyl, 2-propyl-2-pentenyl or 2-hydroxy-2-propylpentyl. 4. A process according to claim 1 wherein the unsaturated compound has the formula II wherein R is 2-propylene pentyl. 5. Intermediates of the formula: a IV anti IV-syn wherein R = 2-propylpentyl which may have one, two or three internal unsaturated bonds or 2-substituted-2-propylpentyl which may have one 5 or two internal unsaturated bonds and wherein the substituent at the 2 position is a leaving group. 6. The intermediates of claim 5, wherein the leaving group is selected from 10 hydroxyl, alkoxyl, acetoxyl or tetrahydropyranyloxy groups. 7. Intermediates according to claim 5 of formula IV wherein R is 2-propylpentyl, 2-propyl-1-pentenyl, 2-propyl-2-pentenyl or 2-hydroxy-2-propylpentyl. 8. Intermediates according to claim 5 of formula V wherein R is 220 propylpentyl.