Synthesis and purification of 3,3-dimethylbutyramide through the oxidation of 1-chloro-3,3-dimethylbutane dimethylsulfoxide (options)

 

(57) Abstract:

The invention relates to methods of obtaining and purification of 3,3-dimethylbutyramide. The first method of obtaining comprises contacting 1-chloro-3,3-Dimethylbutane and dimethyl sulfoxide in the presence of inorganic bromide in amounts of 0.05 to 10 equivalents. or inorganic iodide in an amount of 0.01-1.5 EQ. and in the presence of a base in a quantity of 1-10 EQ. Another way to carry out the contacting tert-butyl chloride and ethylene in the presence of aluminum chloride to obtain 1-chloro-3,3-Dimethylbutane, the allocation of 1-chloro-3,3-Dimethylbutane and hold the contacts 1-chloro-3,3-Dimethylbutane and dimethyl sulfoxide to obtain 3,3-dimethylbutyramide in the conditions of the first method. Received by the first and second methods, the target product was then purified by treatment in aqueous solution of sodium bisulfite in not miscible with water solvent, washing and contacts when heated with aqueous organic base or an aqueous inorganic acid, followed if necessary, by distillation. The method allows to obtain 3,3-dimethylbutyramide reproducible and highly efficient manner with a high purity. 2 C. 16 h. p. F.-ly.

The scope of the invention

Art

1-Chloro-3,3-dimethylbutan can be synthesized by treatment of tert-butyl chloride and ethylene chloride aluminum, as reported in Ada Chem. Scand., volume 13 (1959), page 612, the disclosure of which is included in the description by reference. About the oxidation of benzylchloride dimethylsulfoxide to benzaldehyde was reported in the Journal of American Chemical Society, volume 81 (1959), pages 4113-4114, and Journal of Organic Chemistry, volume 24 (1959), pages 1792-1793. Oxidation of dimethylsulfoxide primary halides, activated neighboring carbonyl group to the corresponding aldehydes was reported in the Journal of American Chemical Society, volume 79 (1957), page 6562, and Journal of Organic Chemistry, volume 23 (1958), page 1563.

Oxidation of primary aliphatic chlorides and bromides dimethylsulfoxide in the presence of 1.5 equivalents of NaI was reported in Synthetic Communications, volume 16 (1986), pages 1343-1346. It was reported that the reaction leads to the corresponding aldehydes with the release of 56-96%. This article does not describe the oxidation of 1-chloro-3,3-Dimethylbutane and implicit assumptions that a catalytic amount of iodide is effective for oxidation. In Journal of American Chemical Society, volume 81 (1959), pages 4113-4114, and Tetrahedron Letters (1974), pages 917-920 described that simple primary chlorides and bromides can envelope the s.

In U.S. patent 4175204 described the use of sodium bromide activated allyl chloride. Substituted allyl chloride was oxidized to its corresponding aldehyde using DMSO in the presence of catalytic amounts of sodium bromide.

3,3-Dimethylbutyramide is an intermediate compound, which is useful when receiving sweetener - 1-methyl ester N-[N-(3,3-dimethylbutyl)-L-aspartyl] -L-phenylalanine, and disclosed in U.S. patent 5480668 and U.S. patent 5510508. Commercially available 3,3-dimethylbutyramide are currently using methods that are very expensive and lead to a product that is not commercially feasible.

There are several ways to obtain 3,3-dimethylbutyramide by oxidation of 3,3-dimethylbutanol, which are described in EP 0391652, EP 0374952, Journal of Organic Chemistry, volume 54, page 570 (1989), Journal of Organic Chemistry, volume 61, page 2918 (1996) and Journal of American Chemical Society, volume 103, page 4473 (1981). However, nothing was reported about the method by which you can obtain 3,3-dimethylbutyramide by oxidation of 1-chloro-3,3-Dimethylbutane.

In addition, the crude oxidation product 1-chloro-3,3-Dimethylbutane using DMSO usually contains dimethyl disulfide and dimethyl sulfide, among other ser(boiling point 109o(C) from 3,3-dimethylbutyramide (boiling point 104-106oC) because their boiling points are very close. Pollution of 3,3-dimethylbutyramide even trace amounts of organic sulfuric impurities is highly undesirable for its application in the synthesis of 1-methyl ester N-[N-(3,3-dimethylbutyl)-L-aspartyl]-L-phenylalanine, which is usually obtained by hydrogenation of a mixture of 3,3-dimethylbutyramide and aspartame in the presence of a catalyst based on a noble metal. It is well known that such catalysts can be deactivated by organic sulfur compounds. Thus, any organic sulfur impurity must be removed from 3,3-dimethylbutyramide to its hydrogenation with aspartame. Accordingly, it is desirable to develop a cleaning method, which can remove all impurities, including sulfur-containing compounds from a crude product of 3,3-dimethylbutyramide.

The literature describes the purification of aldehydes by transformations in solid adduct of the aldehyde/bisulfite. As a General reference for this technique in the description included a reference to "Purification of Laboratory Chemicals" (Pergamon Press, 1988), pages 60-61.

In Chemical Pharmaceutical Bulletin, vol 26 (1978), pages 3233-3236 included in the description in which bromide with orthoformiate by its conversion to the adduct of 3,3-dimethylbutyramide/sodium bisulfite and subsequent regeneration of the aldehyde aqueous sodium bicarbonate. This treatment includes the following stages: mixing a mixture of selected crude product and an aqueous solution of sodium bisulfite at room temperature overnight; the selection of the solid adduct of 3,3-dimethylbutyramide/sodium bisulfite by filtration; washing the selected solid adduct and the aqueous filtrate simple ether; Association washed dedicated solid adduct with a water filtrate and sodium bicarbonate with the formation of the mixture; the distillation of this mixture with water vapor. Further steps lead to a purified 3,3-dimethylbutyramide. However, this method is not adapted for the removal of trace quantities of organic sulfur compounds from aldehyde and may not result in a 3.3-dimethylbutyramide free of organic sulfur contaminants, which is necessary for the synthesis of 1-methyl ester N-[N-(3,3-dimethylbutyl)-L-aspartyl]-L-phenylalanine.

Accordingly, it is very desirable way to obtain 3,3-dimethylbutyramide, which is inexpensive and gives a product of greater purity.

Brief description of the invention

This invention relates to a method for producing 3,3-dimethylbutyramide by contacting 1-chloro-3,3-Dimethylbutane and dimethyl sulfoxide of Vesta base, followed by purification through adduct of aldehyde bisulfite to obtain 3,3-dimethylbutyramide. As a solvent in this reaction it is possible to use organic compounds, including 1-chloro-3,3-dimethylbutan.

The invention also relates to a method for producing 3,3-dimethylbutyramide by contacting tert-butyl chloride and ethylene in the presence of aluminum chloride, effective to produce 1-chloro-3,3-Dimethylbutane, separation is obtained 1-chloro-3,3-Dimethylbutane and contacting the selected 1-chloro-3,3-Dimethylbutane with dimethylsulfoxide in the presence of an effective amount of inorganic bromide or iodide in the presence of an effective amount of a base, followed by purification through adduct of aldehyde bisulfite to obtain 3,3-dimethylbutyramide.

The method of the present invention allows to obtain 3,3-dimethylbutyramide reproducible and highly efficient manner with greater purity, so that the use of aldehyde upon receipt of sweetener derived from aspartame, is commercially viable.

Detailed description of the invention

The present invention 3,3-dimethylbutyramide is formed by the oxidation of 1-chloro-3,3-dimethylbutanoate-sulfoxide (DMSO) in the presence of an effective amount of inorganic br>1-Chloro-3,3-dimethylbutan, DMSO and the halide is usually in contact at a temperature in the range of from about 60oWith up to approximately 200oC, preferably from about 120oWith up to about 160oC and most preferably from about 130oWith approximately 150oC.

1-Chloro-3,3-dimethylbutan and DMSO is used usually in a ratio of from about 1: 100 by weight to about 1:1 by weight, preferably from about 1:20 by weight to about 1:2 by weight, most preferably from about 1:10 by weight to about 1:3 by weight.

Inorganic bromide or iodide, preferably represents a sodium iodide, potassium iodide, magnesium iodide, zinc iodide, lithium iodide, calcium iodide, aluminum iodide, ammonium iodide, of tetraalkylammonium iodide, sodium bromide, potassium bromide, magnesium bromide, zinc bromide, lithium bromide, calcium bromide, aluminum bromide, ammonium bromide, the bromide of tetraalkylammonium. The ratio of inorganic bromide/1-chloro-3,3-dimethylbutan is usually in the range from 0.05 to about 10 equivalents, preferably from 0.2 to 2 equivalents, and most preferably from 0.4 to 1 equivalent. The ratio of inorganic iodide/1-chloro-3,3-dimethylbutan is usually in the range from 0.01 to use the.

The base is selected from inorganic or organic bases. Also effective mixture of bases. Inorganic base preferably is a sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, zinc oxide, aluminum oxide, zinc carbonate, magnesium oxide, calcium oxide, calcium carbonate, magnesium carbonate, potassium phosphate (primary, secondary and tertiary), sodium phosphate (primary, secondary and tertiary), ammonium phosphate, calcium phosphate, magnesium phosphate or ammonia. Organic base preferably is a tertiary amine, a secondary amine or a derivative of pyridine. The ratio of base/1-chloro-3,3-dimethylbutan is usually in the range of from 1 to about 10 equivalents, preferably 1 to 5 equivalents, and most preferably from 1 to 2 equivalents.

The reaction allowed to proceed for a period of time from about 30 minutes to about 2880 minutes, preferably from about 180 minutes to about 1440 minutes, most preferably from about 360 minutes to about 840 minutes.

The crude aldehyde was collected and purified through its adduct with sodium bisulfite using is not miscible with water solvent. Treatment includes Ore of sodium bisulfite was stirred for some time.

B. Solid adduct was isolated by filtration and the solid is thoroughly washed with a mixture of alcohol and is not miscible with water solvent.

C. the Solid was dried.

, 3,3-Dimethylbutyramide was regenerated by heating a mixture of dried solid adduct of the aldehyde/bisulfite and water, inorganic base or acid, followed by distillation.

3,3-Dimethylbutyramide obtained and purified by the methods of the present invention, sufficiently pure for use in the synthesis of 1-methyl ester N-[N-(3,3-dimethylbutyl)-L-aspartyl]-L-phenylalanine. The selection of 3,3-dimethylbutyramide from the crude mixture was usually more than 80%. Both the first and second non-miscible with water, the solvent in the stages a and B preferably is a simple ether, hydrocarbon compound, complex ether or a mixture of the above solvents. Mixing time on stage And is from about 10 minutes to about 1440 minutes, preferably from about 20 minutes to about 600 minutes, most preferably from about 30 minutes to about 360 minutes. Alcohol at the stage B is preferably methyl alcohol, ethyl alcohol, propyl alcohols, butyl th acid, phosphoric acid, sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, calcium carbonate. Heating of the mixture at the stage of G is carried out until a temperature from about 40oC to the boiling point of the mixture.

The precursor of 1-chloro-3,3-Dimethylbutane can be obtained in any convenient way, such as processing of tert-butyl chloride and ethylene acid catalyst such as aluminium chloride, iron trichloride and solid acid. Thus obtained 1-chloro-3,3-dimethylbutan then treated with DMSO in the manner described above to obtain 3,3-dimethylbutyramide.

The following examples are intended to illustrate the preferred alternative embodiment of the present invention and in no way limit the invention.

Example 1.

Obtain 1-chloro-3,3-Dimethylbutane.

Three-neck round bottom flask of 250 ml was supplied with a mechanical stirrer, the input gas and the outlet for gas, connected to a bubbler. Into the flask was loaded of 57.5 g of tert-butyl chloride and cooled to -20oC. was Added 0.88 g of anhydrous aluminum chloride was introduced ethylene. The reaction rate was controlled either by regulating the mixing, ALOS (after about 45 minutes), ethylene was removed. The mixture decantation in 40 ml of water. The organic layer was separated, obtaining the crude product (75 g, purity 80-85%). Fractional distillation at 111-115oWith gave 52,5 g (70%) of pure 1-chloro-3,3-Dimethylbutane.

Example 2.

Oxidation of 1-chloro-3,3-Dimethylbutane DMSO (dimethylsulfoxide)/NaI.

In a round bottom flask of 100 ml was loaded 2.0 g of 1-chloro-3,3-Dimethylbutane, 2.0 g of sodium bicarbonate, 1.0 g of NaI and 20 g of dimethyl sulfoxide-d6. The flask was purged with nitrogen and heated to 140oC for 2.5 hours. 1H NMR of the reaction mixture showed that 62% of 1-chloro-3,3-Dimethylbutane turned 3.3-dimethylbutyramide.

Example 3.

Oxidation of 1-chloro-3,3-Dimethylbutane DMSO/CVG.

In a round bottom flask of 100 ml was loaded 3.1 g of 1-chloro-3,3-Dimethylbutane, 2.1 g of sodium bicarbonate, 1.5 g of KBr and 18 g of dimethyl sulfoxide-d6. The flask was purged with nitrogen and heated to 145oWith over 4.5 hours.1H NMR of the reaction mixture showed that the yield of 3,3-dimethylbutyramide amounted to 70%.

Example 4.

Oxidation of 1-chloro-3,3-Dimethylbutane DMSO/NaBr.

In a round bottom flask of 500 ml, provided with a device for fractional distillation, download of 46.1 g of 1-chloro-3,3-di-methylbutane, 23 g bromely in the oil bath to 140-150oC (bath temperature 135-140oC) in nitrogen atmosphere 12-14 hours, during which time the flask-the receiver has collected some of the low-boiling fraction (mainly dimethyl sulphide). With regard to the remaining mixture created a vacuum and a new receiver collected crude aldehyde product. The weight of this crude product was 31.6 g (80% of 3,3-dimethylbutylamino).

Example 5.

Purification of the crude 3,3-dimethylbutyramide.

To the mixture (i) of 30.6 g of a crude product of example 4 and (ii) 240 ml of methyl tert-butyl ether (MTBE), cooled using a water bath with ice, was added dropwise over 20 minutes with vigorous stirring, the solution obtained from 30 g of sodium bisulfite and 60 ml of water. After adding sodium bisulfite white solid fell out of solution. Thus obtained suspension was stirred for an additional 80 minutes, continuing cooling with ice. This stirred cold mixture was filtered and washed the remaining solid substance 100 ml of MTBE and 2 x 100 ml of a 60/40 (vol/vol) MTBE/methanol. The solid was dried in a vacuum oven (40o(C) during the night. The mass of dry solids amounted to 48.0 g

In a round bottom flask of 250 ml was loaded (i) of 40.0 g of dry solid vested with purity, sufficient for the synthesis of 1-methyl ester N-[N-(3,3-dimethylbutyl)-L-aspartyl]-L-phenylalanine. The yield was 58% based on 1-chloro-3,3-dimethylbutan.

Specialists in the art will be obvious other changes and modifications. This invention is not limited, except that given in the claims.

1. The method of obtaining 3,3-dimethylbutyramide, comprising contacting 1-chloro-3,3-Dimethylbutane and dimethyl sulfoxide in the presence of inorganic bromide in amounts of 0.05 to 10 equivalents or inorganic iodide in an amount of 0.01-1.5 EQ and in the presence of a base in an amount of 1-10 equivalents.

2. The method according to p. 1, in which the mentioned inorganic bromide or inorganic iodide is sodium iodide, potassium iodide, magnesium iodide, zinc iodide, lithium iodide, calcium iodide, aluminum iodide, ammonium iodide, of tetraalkylammonium iodide, sodium bromide, potassium bromide, magnesium bromide, zinc bromide, lithium bromide, calcium bromide, aluminum bromide, ammonium bromide or bromide of tetraalkylammonium.

3. The method according to p. 1 in which the said base is a sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, zinc oxide, zinc carbonate,CNY potassium phosphate, tertiary phosphate, potassium primary phosphate, secondary sodium phosphate, tertiary sodium phosphate, ammonium phosphate, calcium phosphate, magnesium phosphate, ammonia, tertiary amine, secondary amine, a derivative of pyridine or a mixture thereof.

4. The method according to PP.1, 2 or 3, in which the mentioned stage contacting is carried out at a temperature of from about 60C to about 200C.

5. The method according to p. 1, additionally comprising mixing 3,3-dimethylbutyramide with the first is not miscible with water solvent and an aqueous solution of sodium bisulfite, effective to obtain bisulfite sediment 3,3-dimethylbutyramide; washing mentioned bisulfite precipitate a mixture of alcohol and the second is not miscible with water solvent and contacting with the heating referred washed bisulfite precipitate with aqueous inorganic base or an aqueous inorganic acid, effective to obtain purified 3,3-dimethylbutyramide.

6. The method according to p. 5, further comprising a stage distillation stage after contact, where distillation is effective for the allocation referred purified 3,3-dimethylbutyramide.

7. The method according to p. 5, in which the first is not miscible with water races is oterom first is not miscible with water, the solvent is a simple ester, hydrocarbon, an ester or a mixture thereof and the second is not miscible with water, the solvent is a simple ether, a hydrocarbon, an ester or a mixture thereof.

9. The method according to p. 5, in which the aforementioned aqueous inorganic base or an aqueous inorganic acid is an aqueous solution of hydrochloric acid, sulfuric acid, phosphoric acid, sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate or calcium carbonate.

10. The method of obtaining 3,3-dimethylbutyramide, including the stage of (a) contacting tert-butyl chloride and ethylene in the presence of aluminum chloride to obtain 1-chloro-3,3-Dimethylbutane; (b) allocation obtained 1-chloro-3,3-Dimethylbutane and (C) contacting the selected 1-chloro-3,3-Dimethylbutane with dimethylsulfoxide in the presence of inorganic bromide in amounts of 0.05 to 10 equivalents or inorganic iodide in an amount of 0.01-1.5 EQ and in the presence of a base in an amount of 1-10 equivalents.

11. The method according to p. 10, in which the mentioned inorganic bromide or inorganic iodide is sodium iodide, potassium iodide, magnesium iodide, zinc iodide, lithium iodide, calcium iodide, aluminum iodide, ammonium iodide, of tetraalkylammonium iodide, bromide on the bromide of tetraalkylammonium.

12. The method according to p. 10, in which the said base is a sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, zinc oxide, zinc carbonate, magnesium oxide, calcium oxide, aluminum oxide, magnesium carbonate, calcium carbonate, primary phosphate, potassium secondary phosphate, potassium tertiary phosphate, potassium primary phosphate, secondary sodium phosphate, tertiary sodium phosphate, ammonium phosphate, calcium phosphate, magnesium phosphate, ammonia, tertiary amine, secondary amine, a derivative of pyridine or a mixture thereof.

13. The method according to PP.10, 11 or 12, in which the mentioned stage contacting is carried out at a temperature of from about 60C to about 200C.

14. The method according to p. 10, additionally comprising mixing 3,3-dimethylbutyramide with the first is not miscible with water solvent and an aqueous solution of sodium bisulfite, effective for the formation of bisulfite sediment 3,3-dimethylbutyramide; washing mentioned bisulfite precipitate a mixture of alcohol and the second is not miscible with water solvent and contacting with the heating washed bisulfite precipitate with aqueous inorganic base or an aqueous inorganic acid, effective to obtain purified 3,3-deaktivovana, where distillation is effective for the allocation referred purified 3,3-dimethylbutyramide.

16. The method according to p. 14, in which the first is not miscible with water, the solvent is the same as the second is not miscible with water solvent.

17. The method according to p. 14, in which the first is not miscible with water, the solvent is a simple ether, a hydrocarbon, an ester or a mixture thereof and the second is not miscible with water, the solvent is a simple ether, a hydrocarbon, an ester or a mixture thereof.

18. The method according to p. 14, in which the aforementioned aqueous inorganic base or an aqueous inorganic acid is an aqueous solution of hydrochloric acid, sulfuric acid, phosphoric acid, sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate or calcium carbonate.

 

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