EP0832059A1

EP0832059A1 - Method for the preparation of an n-(2-bromoalkyl)-amide derivative

Info

Publication number: EP0832059A1
Application number: EP96917728A
Authority: EP
Inventors: Gerardus Karel Maria Verzijl; Quirinus Bernardus Broxterman; Henricus Leonardus Marie Elsenberg
Original assignee: DSM NV
Current assignee: Koninklijke DSM NV
Priority date: 1995-06-14
Filing date: 1996-06-13
Publication date: 1998-04-01
Also published as: WO1997000237A1; BE1009427A3; JPH11507665A

Abstract

The invention relates to a method for the preparation of an N-(2-bromoalkyl)-amido derivative according to formula (1), wherein an alkenically unsaturated compound (alkene) is brought into contact with a donor of a positive bromine ion and a nitrile in the presence of water or an acid, preferably sulphuric acid. The invention also relates to the use of an N-(2-bromoalkyl)-amido derivative thus obtained in the preparation of 1,2-aminoalcohols, β-amido-α-hydroxycarboxylic acids, β-amino acids, β-amido acids, β-aminonitriles, β-amidonnitriles, β-amido-α-hydroxynitriles, β-aminoamides, β-amidoamides or β-amido-α-hydroxyamides, in particular a method for the preparation of a 1,2-aminoalcohol, an N-(2-bromoalkyl)-amido derivative first being subjected to a ring closure, preferably under acidic conditions, and optionally subsequently being subjected to a preferably acidic hydrolysis. Such 1,2-aminoalcohols can suitably be used in the preparation of known pharmaceuticals. A particularly attractive method for the preparation of a 1,2-aminoalcohol is obtained if the total route from the alkene is carried out without the products formed intermediately being isolated in between.

Description

PROCESS FOR THE PREPARATION OF AN N-(2-BROMOALKYL.-AMIDE DERIVATE

The invention relates to a method for the preparation of an N-(2-bromoalkyl)-amido derivative, wherein an alkenically unsaturated compound is brought into contact with a donor of a positive bromine ion, in the presence of a nitrile and water or an acid.

Such a method has been described in J. Beger et al., Journal fur praktische Chemie, Band 311 (1969) p. 15-35, wherein the donor used, of a positive halogen, in most cases is Cl₂ and, occasionally, Br₂. A drawback of the method described is that the yield, depending on the substrate chosen, is low to very low.

The object of the invention is a method wherein the desired N-(2-bromoalkyl)-amido derivative is obtained in a relatively high yield.

This is achieved, according to the invention, by using, as the donor of a positive halogen, a N-bromo compound from the group consisting of N-bromoimides, N- bromohydantoins and N-bromoamides.

The fact is that, surprisingly, it was found that with the aid of such N-bromo compounds as a donor of positive halogens, high yields can be achieved with a wide range of alkenically unsaturated compounds. The use of Br₂ or 5,5-dibromobarbituric acid as the donor of positive bromine ions led to far poorer results, for example. It was also found that N-bromo compounds gave better results than corresponding iodine or chlorine compounds. N-(2-bromoalkyl)-amido derivatives which can be prepared by means of the method according to the invention can be represented by the general formula (1)

The choice of R_x, R₂, R₃, R₄ and R₅ in this formula is not particularly critical. R_x, R₂, R₃ and R₄ are defined by the choice of the alkenically unsaturated compound, within the scope of this invention sometimes simply referred to as alkene,

which is used as a starting material in the method according to the invention; they may, for example, each be chosen, independently of one another, from H, a hydrocarbon group, for example an alkyl group, alkenyl group, aryl group, alkaryl group or aralkyl group, in particular a hydrocarbon group having 1-20 C atoms, or _L and R₃ or alternatively R₂ and R₄ may, together with the C atoms to which they are bound, form a ring; at the same time R_x and/or R₂ may represent an acid group, a nitrile or an amide. The choice of R₅ is not critical either; R₅ may represent, for example, H, a hydrocarbon group, for example an alkyl group, alkenyl group, aryl group, alkaryl group or aralkyl group having 1-20 C atoms, an amino group or an imino group. The said hydrocarbon groups, amino groups or imino groups may optionally be substituted with, for example, one or more alkyl groups or aryl groups having 1-10 C atoms, one or more halogen atoms and/or one or more amino groups. The nitrile to be used is largely defined by the choice of R₅. The nitrile chosen is usually R₅-C≡N, but other compounds which, after the bromination reaction, afford the desired R₅-amido substituent can also be employed. Thus, for example, the nitrile NC- N=C(NH₂)₂ can be used to obtain an N-(2-bromoalkyl)- amido derivative with R₅=NH₂. The nitrile used is preferably acetonitrile.

The amount of nitrile to be used is preferably chosen to be as low as possible, in particular lower than 30 molar equivalents, preferably 1-10 molar equivalents of nitrile referred to alkene. Suitable donors of positive halogens which can be used are, for example, N-dibromohydantoins, N- bromosuccinimides, and N-bromoacetamide. Preference is given to the use of 1,3-dibromo-5,5-dimethylhydantoin (DBDMH). The amount of water and/or acid present in the reaction mixture is usually between 0.5 and 4 molar equivalents, if only water is used, and between 0.5 and 10 acid equivalents if only acid is used, calculated on the basis of the amount of alkene. The term acid equivalents, within the scope of the present invention, refers to equivalents of H⁺; thus, 1 molar equivalent of sulphuric acid corresponds to 2 acid equivalents, and 1 molar equivalent of hydrochloric acid corresponds to 1 acid equivalent. In order for complete conversion to be achieved, the total amount of water and/or acid should be at least 1 equivalent of water and/or acid referred to alkene. Preferably, 1-3 molar or acid equivalents, respectively, of water and/or acid referred to alkene are used. If, in addition to water, an acid is employed, the amount of water present in the reaction mixture is preferably kept as low as possible.

Preferably, an acid is present in the reaction mixture. The acid used usually comprises mineral or organic acids, for example sulphuric acid, oleum, phosphoric acid, polyphosphoric acid, perchloric acid, substituted sulphonic acids, for example p- toluenesulphonic acid and methanesulphonic acid, and carboxylic acids, for example acetic acid, formic acid, benzoic acid and pivalic acid. Preference is given to the use of a non-nucleophilic or weakly nucleophilic acid. The greatest preference is given to sulphuric acid. The amount of acid is not critical and is often between 0 and 10 acid equivalents of acid referred to alkene. Larger amounts of acid, for example the use of an acid as a solvent, are indeed possible in principle, but are not particularly advantageous in the reaction. Preferably, 1-3 acid equivalents of acid are used.

If required, a solvent is also used in this reaction. Possible solvents include, for example, acids, in particular sulphuric acid and acetic acid; anhydrides, for example acetic anhydride; ethers, for example di-n-butyl ether and hydrocarbons which may or may not be substituted, in particular halogenated, for example hexane, toluene, dichloromethane, chloroform, tetrachloromethane and nitrobenzene. Preferably, however, no additional solvent is used.

The temperature at which the above-described reaction is carried out is usually between -50 and +50°C, preferably between -20 and +30°C. The Ν-(2-bromoalkyl)-amido derivative prepared according to the invention can, for example, be used in the preparation of β-amido acids, β-amino acids and β-amido-α-hydroxycarboxylic acids. To this end, an α-β-unsaturated acid, as the alkenically unsaturated compound, is first converted, by means of the method according to the invention, into an α-bromo- β-amido acid, followed by a reduction to the β-amido acid; hydrolysis of the β-amido acid subsequently affords the corresponding β-amino acid. In the same way it is possible to prepare, for example, β-aminonitril- es, β-amidonitriles, β-amido-α-hydroxynitriles, β- aminoamides, β-amidoamides and β-amido-α-hydroxyamides from α,β-unsaturated nitriles or amides. The ring closure of, for example, the α-bromo-β-amidocarboxylic acid to give the corresponding oxazoline, followed by mild hydrolysis, affords the corresponding β-amido-α- hydroxycarboxylic acid.

An Ν-(2-bromoalkyl)-amido derivative, prepared according to the invention from an alkene wherein R_lf R₂, R₃, R₄ represent H or a hydrocarbon group, can be employed particularly suitably in the preparation of 1,2-aminoalcohols. To this end the N-(2- bromoalkyl)-amido derivative is subjected to a ring closure, preferably under acidic conditions, followed by hydrolysis. The hydrolysis of the ring closure product to give the desired 1,2-amino alcohol preferably takes place under acidic conditions, because in an acidic environment a higher yield can be achieved than if these steps are carried out in a basic environment and, moreover, no changes in pH need be carried out during the reaction of the alkene to give the 1,2- aminoalcohol.

The method according to the invention can be employed particularly suitably in the preparation of pharmaceuticals. The preparation of taxol, a known agent for the treatment of tumours, may, for example, suitably involve the use of 3-phenylisoserine, prepared from cinnamic acid by means of the method according to the invention, as a building block. The method according to the invention can also be used in the preparation of cis-l-amino-2-indanol from indene. Cis- l-amino-2-indanol is employed, for example, in the preparation of pharmaceuticals, in particular in the preparation of medicines for the treatment of AIDS, for example HIV-protease inhibitors such as described, for example, by Thompson et al. in J. Med. Chem., Vol. 35 ( 1992 ) , 1685 .

Of particular importance for such applications is the (2R,1S) enantiomer. This enantiomer can be obtained in a simple manner from racemic cis-1- amino-2-indanol, for example via a classical racemate resolution with the aid of an optically active resolving agent.

The term acidic conditions for ring closure and hydrolysis refers, within the scope of the invention, to a pH lower than 7, in particular between -3 and +3, preferably between -1 and +1. Such an acidic environment can be achieved, for example, by the addition of an acid, in particular a strong acid.

Mineral or organic acids may be used as acid. Examples of suitable acids are the acids as described above within the scope of the bromination reaction. Preferably, strong mineral acids are used, for example sulphuric acid, hydrochloric acid, phosphoric acid or strong organic acids, for example sulphonic acids, in particular methanesulphonic acid or p-toluenesulphonic acid.

The choice of the solvent for the ring closure and the hydrolysis is not critical and may, for example, be water or a water-miscible solvent which is inert under the reaction conditions and in which water is dissolved. Preferably, water is used. The amount of solvent to be employed is not critical and can be determined by those skilled in the art in a simple manner. The temperature at which the ring closure and the hydrolysis are carried out is not critical and will usually be between 0 and 120°C, preferably between 40 and 105°C.

The N-(2-bromoalkyl)-amido derivative, the 0- acyl derivative of the 1,2-aminoalcohol formed as an intermediate during the hydrolysis, the acyl group being derived from the nitrile used, and the 1,2- aminoalcohol can, if required, each be obtained separately according to methods known to those skilled in the art. A particularly suitable method for the preparation of the 1,2-aminoalcohol is accomplished if the preparation of the N-(2-bromoalkyl)amido derivative from the alkene, the ring closure and the hydrolysis are carried out without the isolation, in between, of the products formed intermediately, i.e. if, for example, the conversion of indene into cis-l-amino-2- indanol is carried out via a so-called one-pot reaction. This is possible because, as well as the preparation of the 1,2-aminoalcohol, the ring closure and the hydrolysis in an acidic environment were found to afford a high yield and because it was found that the isolation and purification of the intermediate products is unnecessary for obtaining a good product with a high yield, an additional advantage being provided thereby. A further advantage results from the fact that no pH changes (from acidic to basic environment and vice versa) were found to be necessary, which makes it possible to implement a process with a lower salt load. The invention will be explained with reference to the following Examples, without being limited thereto.

Example I to VII inclusive Reaction of 1,3-dibromo-5-5-dimethylhydantoin with an alkene in acetonitrile and sulphuric acid

12.5 g of concentrated sulphuric acid was weighed into 100 ml of acetonitrile. The solution was cooled to 0°C. Into this solution 0.95 g of 1,3- dibromo-5,5-dimethylhydantoin and, slowly, 0.006 mol of the alkene were metered in. Said metering in of the alkene against l,3-dibromo-5,5-dimethylhydantoin was repeated 20 times. The reaction was monitored by means of TLC in hexane/ethyl acetate (8/2).

100 ml of water were added to the reaction mixture, and the acetonitrile was removed under reflux. In the process, the temperature slowly rose to 105°C. The hydrolysis was continued for 3 hours at 105°C and the mixture was cooled to room temperature. The water layer was purified of apolar organic contaminants by means of extraction with CH₂C1₂ and alkalified to pH 12 with a 50% strength aqueous ΝaOH solution. The product was obtained by means of extraction with CH₂C1₂. The results are given in the Table.

Table

Exam¬ Alkene 1,2-Amino- Yield (%)^1} ple alcohol

I indene cis-l-amino-2- 72 indanol

II styrene phenylglycinol 60

III trans- threo-2-amino- 80 stilbene 1,2-diphen l¬ ethanol

IV cydohexene cis-2-amino- 85 cyclohexanol

V allylbenzene phenylalaninol ₄₄2)

VI trans-p- threo-3-(4- 100 methoxy- methoxyphenyl)- cinnamic acid 3-amino-2- hydroxypropionic acid

VII trans- threo-3-phenyl- 78 cinnamic acid isoserine

1) Yield of isolated 1,2-aminoalcohol (ΝMR-pure)

2) 19% of l-amino-3-phenyl-2-propanol is also obtained.

Example VIII

Into 100 ml of acetonitrile an initial charge was introduced, with cooling to 0°C, of 0.121 mol of concentrated sulphuric acid to which 0.121 mol of water had been added. In this solution, 0.0666 mol of 1,3- dibromo-5,5-dimethylhydantoin was suspended. Then, at 0°C over a period of 0.5 hours, 0.121 mol of indene was metered in, stirring continuing for a further 0.5 hours. 100 ml of water were added to this mixture, whereupon the acetonitrile was distilled off. The aqueous solution was refluxed for 3 hours. After extraction with dichloromethane the aqueous phase was set to pH 12 with 50% strength aqueous sodium hydroxide. The product was obtained by means of filtration. Yield: 50%.

Example IX Into 100 ml of acetonitrile an initial charge was introduced, with cooling to 0°C, of 0.121 mol of concentrated sulphuric acid. In this solution, 0.133 mol of N-bromosuccinimide was suspended. Then, at 0°C over a period of 0.5 hours, 0.121 mol of indene was metered in, stirring continuing for a further 0.5 hours. 100 ml of water were added to this mixture, whereupon the acetonitrile was distilled off. The aqueous solution was refluxed for 3 hours. After extraction with dichloromethane the aqueous phase was set to pH 12 with 50% strength aqueous sodium hydrox¬ ide. The product was obtained by means of filtration. Yield: 50%.

Example X Into 100 ml of acetonitrile an initial charge was introduced of 0.121 mol of water. In this solution, 0.0666 mol of 1,3-dibromo-5,5-dimethylhydantoin was suspended. Then, very slowly, at 0°C over a period of approx. 60 minutes, 0.121 mol of indene was metered in, stirring continuing until the indene was completely gone. 100 ml of water were added to this mixture, and the acetonitrile was then distilled off. The aqueous solution was refluxed for 3 hours. After extraction with dichloromethane the pH of the aqueous phase was set to 12 with 50% strength aqueous sodium hydroxide. The product was obtained by means of filtration. Yield: 49% .

Example XI

Into 100 ml of acetonitrile, 0.121 mol of indene to which 0.121 mol of water had been added, were introduced, with cooling to 0°C, as an initial charge. 0.0666 mol of 1,3-dibromo-5,5-dimethylhydantoin was slowly metered into this solution. Then, over a period of approximately 15 minutes, 0.145 mol of concentrated sulphuric acid was slowly metered in. 100 ml of water were added to this mixture, and the acetonitrile was then distilled off. The aqueous solution was refluxed for 3 hours. After extraction with dichloromethane the pH of the aqueous phase was set to 12 with 50% strength aqueous sodium hydroxide. The product was obtained by means of filtration. Yield: 48%.

Example XII

Into 100 ml of acetonitrile an initial charge was introduced, with cooling to 0°C, of 0.121 mol of concentrated sulphuric acid to which 0.242 mol of water had been added. In this solution, 0.133 mol of 1,3- dibromo-5,5-dimethylhydantoin was suspended. Then, at 0°C over a period of 0.5 hours, 0.242 mol of indene was metered in, stirring continuing for a further 0.5 hours. 100 ml of water were added to this mixture, and the acetonitrile was then distilled off. The aqueous solution was refluxed for 3 hours. After extraction with dichloromethane the pH of the aqueous phase was set to 12 with 50% strength aqueous sodium hydroxide.

The product was obtained by means of filtration. Yield: 40%.

Example XIII A solution of 39.3 g (0.4674 mol) of dicyano- diamide and 26.0 g (0.2547 mol) of concentrated H₂S0₄ in 65 ml of formamide was cooled to 0°C. Into the solution, alternately, 3.28 g (0.0115 mol) of DBDMH and, slowly, 3.0 g (0.0233 mol) of indene were metered 10 times. The reaction mixture was stirred for a further 1 hour at 0°C. The reaction was monitored for indene with the aid of TLC in hexane/ethyl acetate (8/2). The remaining indene was additionally converted with an additional portion of 2.0 g (0.007 mol) of DBDMH. The reaction mixture was admixed with 65 ml of water and stirring continued for a considerable time at 105°C. The aqueous phase was extracted twice at 70 to 90°C and once at 20°C with 100 ml of toluene. In the purified aqueous layer the cis-l-amino-2-indanol content was determined with the aid of HPLC. The calculated yield of cis-l-amino-2-indanol on the basis of indene was calculated at 48%.

Comparative Experiment A

In 25 ml of acetonitrile, 3.40 g (0.033 mol) of concentrated H₂S0₄ were introduced as an initial charge at 0°C. Into this solution, alternately, 0.455 g (0.0016 mol) of 5,5-dibromobarbituric acid and, slowly, 0.185 g (0.0015 mol) of indene (96%) were metered in 10 times. The mixture was stirred for a further 17 hours at 20°C. The reaction mixture was admixed with 25 ml of water and heated to 100°C for several hours. The solution was analysed for its cis-l-amino-2-indanol content. The calculated yield of cis-l-amino-2-indanol on the basis of indene was calculated at 3.2%.

Claims

C L A I M S

1. Method for the preparation of an N-(2-bromoalkyl)- amido derivative, wherein an alkenically un-

5 saturated compound is brought into contact with a donor of a positive bromine ion, in the presence of a nitrile and water or acid, characterized in that the donor used, of a positive halogen, is an N-bromo compound selected from the group 0 consisting of N-bromoimides, N-bromohydantoins and N-bromoamides.

2. Method according to Claim 1, wherein the donor used, of a positive halogen, is 1,3-dibromo-5,5- dimethylhydantoin.

15 3. Method according to Claim 1 or 2, wherein 1-3 acid equivalents of acid are used.

4. Method according to any one of Claims 1-3, wherein the acid used is sulphuric acid.

5. Method according to any one of Claims 1-4, wherein 20 a N-(2-bromoalkyl)-amido derivative of formula (1)

Ri R₃ 9 i i II

Br - C - C - NH - C - R₅ (1)

I I __D R₂ -₄ is prepared, wherein R_x and R₂, independently of one another, represent an H, alkyl, aryl, aralkyl or alkaryl or, together with the C atoms to which they are bound, form a ring (having 4-8 C atoms),

30 or represent an acid group, nitrile group or an amide group; R₃ and R₄, independently of one another, represent an H, alkyl, aryl, aralkyl or alkaryl or, together with the C atoms to which they are bound, form a ring (having 4-8 C atoms);

35 and R_s represents an alkyl group, alkenyl group, an aryl group, an aralkyl group, an alkaryl group, an amino group or an imino group, wherein an alkenically unsaturated compound of formula

with R_1# R₂, R₃ and R₄ as defined above is used.

6. Method according to any one of Claims 1-5, wherein the N-(2-bromoalkyl)-amido derivative obtained is subsequently subjected to a ring closure reaction.

7. Method according to Claim 6, wherein the ring- closed product is subsequently subjected to a hydrolysis.

8. Method according to Claim 6 or 7, wherein the ring closure and/or the hydrolysis take place under acidic conditions.

9. Method according to any one of Claims 6-8, wherein successive steps are carried out without the products formed intermediately being isolated in between.

10. Method according to any one of Claims 6-9, wherein an alkenically unsaturated compound according to formula (2), where R and/or R₂ is an acid group, is used.

11. Method according to any one of Claims 6-9, wherein an alkenically unsaturated compound according to formula (2), where R_x and/or R₂ is an amide group or a nitrile group, is used.

12. Method according to any one of Claims 6-9, wherein cis-l-amino-2-indanol is prepared, starting from indene as the alkenically unsaturated compound.

13. Method for the preparation of optically active cis-(2R,lS)-l-amino-2-indanol, characterized in that the cis-l-amino-2-indanol obtained by means of the method according to Claim 12 is subjected to racemate resolution.

14. Method according to any one of Claims 1-5, wherein the N-(2-bromoalkyl)-amido derivative obtained is subsequently converted into a 1,2-aminoalcohol, a β-amido-α-hydroxycarboxylic acid, a β-amino acid, a β-amido acid, a β-aminonitrile, a β- amidonitrile, a β-amido-α-hydroxynitrile, a β- aminoamide, a β-amidoamide or a β-amido-α-hy- droxyamide.

15. Use of cis-l-amino-2-indanol obtained by means of the method according to Claim 12 or 13 in the preparation of pharmaceuticals, in particular HIV- protease inhibitors.

16. Method as described and explained with reference to the Examples.