JPH11507665A - Method for producing N- (2-bromoalkyl) -amide derivative - Google Patents

Abstract

(57) Abstract: The present invention provides an N- (2-bromoalkyl) -amide derivative according to Chemical Formula 1, Wherein the alkene unsaturated compound (alkene) is contacted with a positive bromine ion donor and a nitrile in the presence of water or an acid, preferably sulfuric acid. The present invention provides an N- (2-bromoalkyl) -amide derivative obtained as described above, using 1,2-amino alcohol, β-amide-α-hydroxycarboxylic acid, β-amino acid, β-amic acid, Used in the preparation of β-aminonitrile, β-amidonitrile, β-amido-α-hydroxynitrile, β-aminoamide, β-amidoamide or β-amido-α-hydroxyamide, especially in the preparation of 1,2-aminoalcohol Also with respect to the process, first the N- (2-bromoalkyl) -amide derivative is subjected to ring closure, preferably in the presence of an acid, and optionally then preferably to acid hydrolysis. Such 1,2-amino alcohols are suitably used for the preparation of known pharmaceuticals. A particularly attractive method of preparing 1,2-amino alcohols is obtained when the entire route from the alkene is carried out without isolation along the way of the intermediately formed product.

Description

DETAILED DESCRIPTION OF THE INVENTIONMethod for producing N- (2-bromoalkyl) -amide derivative The present invention relates to a method for producing an N- (2-bromoalkyl) -amide derivative. In the method, an alkene unsaturated compound is formed in the presence of nitrile and water or an acid. The article is contacted with a positive bromide donor.   Such a method is described in J. Bäger et al., Journal fur praktische Chemi, ed. 311, 1969, pp. 15-35, where the positive The logen ion donor is usually a chlorine molecule and in some cases a bromine molecule .   A disadvantage of the described method is the yield [depending on the selected substarate] ] Is very low to very low.   The object of the present invention is to compare the desired N- (2-bromoalkyl) -amide derivative It is a method that can be obtained with a particularly high yield.   This is because, according to the invention, N-bromoimide is used as a positive halogen ion donor. -Bromination from the group consisting of, N-bromohydantoin and N-bromoamide This is achieved by using a compound.   In fact, surprisingly, such N-bromo as a positive halogen ion donor Compound utilization achieves high yields for a wide range of alkene unsaturated compounds. Was found. For example, bromine molecules as positive bromine ion donors or 5,5- The use of dibromobarbituric acid is rather poor Result. N-bromo compounds have better binding than the corresponding iodine or chlorine compounds. It has also been found to give fruit.   N- (2-bromoalkyl) -amide derivatives that can be prepared according to the present invention Can be represented by the general chemical structural formula (1).   R in this equation₁, R_Two, R_Three, R_FourAnd R_FiveThe choice is not particularly important. R₁ , R_Two, R_Three, And R_FourIs an alkene unsaturated compound (within the scope of the present invention, simply It is sometimes called alkene and is used as a starting material in the method of the present invention. ) Is defined by the choice of They are, for example, each independently of one another hydrogen, hydrocarbon An alkyl group, such as an alkyl group, an alkenyl group, an aryl group, an alkaryl group, or an Selected from aralkyl groups, especially hydrocarbon groups having 1 to 20 carbon atoms, or R₁And R_ThreeOr R instead_TwoAnd R_FourIs the carbon source to which they are attached Form a ring with the child. At the same time, R₁And / or R_TwoIs an acid group, a nitrile or an amine. May be represented. R_FiveThe choice is not particularly important. R_FiveIs For example, hydrogen, a hydrocarbon group, for example, an alkyl group having 1 to 20 carbon atoms, Alkenyl group, aryl group, alkaryl group, or aralkyl group, amino group or It may represent an imino group. The hydrocarbon group, amino group or imino group is, for example, 1 to One or more alkyl or aryl groups having 10 carbon atoms, one or more halogens It can be optionally substituted by an atom and / or one or more amino groups. Should be used The nitrile is R_FiveIt is generally defined by the choice of Nitrile is usually R_Five−C≡N But the desired R after the bromination reaction_Five-Other compounds giving an amide substituent Things can also be used. Thus, for example, the nitrile NC-N = C (NH_Two)_TwoIs R_Five= NH_TwoTo obtain an N- (2-bromoalkyl) -amide derivative Can be   The nitrile used is preferably acetonitrile. Nitrile used The amount to be chosen is preferably chosen as low as possible, in particular for 30 alkenes. Less than the equivalent, preferably 1 to 10 molar equivalents of the nitrile.   Suitable positive halogen donors that can be used in the present invention include, for example, N- Dibromohydantoin, N-bromosuccinimide, and N-bromoacetamido Is. 1,3-Dibromo-5,5-dimethylhydantoin (DBDMH) is preferably used. You.   The amount of water and / or acid present in the reaction mixture is usually based on the amount of alkene. Calculate, if only water is used, 0.5-4 molar equivalents and only acid will be used If 0.5 to 10 acid equivalents. Within the scope of the present invention, the term acid equivalent is defined as proton ( H⁺) Say the equivalent. Thus, one molar equivalent of sulfuric acid is equivalent to two acid equivalents and one molar equivalent Hydrochloric acid corresponds to one acid equivalent. Water and / or acid to achieve complete conversion Is at least one equivalent of water and / or acid to the alkene. Al Water and preferably 1 to 3 equivalents or 1 to 3 acid equivalents, respectively, And / or acids are used.   If an acid is used in addition to water, the amount of water present in the reaction mixture is preferably Or as low as possible.   Preferably, an acid is present in the reaction mixture. The acids used usually include mineral acids. Or organic acids such as sulfuric acid, fuming sulfuric acid, phosphoric acid, polyphosphoric acid, perchloric acid, substituted sulfone Acids, e.g., p-toluenesulfonic acid and metasulfonic acid, and carboxylic acids; For example, acetic acid, formic acid, benzoic acid, and pivalic acid are included. Non-nucleophilic or weak nucleophilic The use of acidic acids is preferred. Most preferred is sulfuric acid. The amount of acid is important Rather, often from 0 to 10 acid equivalents of acid to alkene. Large amounts of acid, for example Although the use of an acid as a solvent is theoretically possible, it is particularly Is not advantageous. Preferably, 1 to 3 acid equivalents of acid are used.   If necessary, a solvent is also used in the reaction. Possible solvents include, for example, Acid, especially sulfuric acid, and acetic acid; anhydrides, such as acetic anhydride; ethers, such as di- n-butyl ether, and substituted or unsubstituted hydrocarbons, Halides, such as hexane, toluene, dichloromethane, chloroform, Tetrachloromethane and nitrobenzene. Preferably, however, No solvent is used.   The temperature at which the above reaction is performed is usually -50 to + 50C, preferably -20 to + 50C. + 30 ° C.   The N- (2-bromoalkyl) -amide derivatives prepared according to the present invention are, for example, For example, β-amic acid, β-amino acid, and β-amide-α-hydroxycarboxylic acid It can be used for synthesis. For this reason, the α-β-unsaturated acid is As a saturated compound, the α-bromo-β-amic acid And then reduced to β-amic acid. The hydrolysis of β-amic acid is Then the corresponding β-amino acid is given. In a similar manner, for example, β-aminonitrile , Β-amido nitrile, β-amido-α-hydroxy nitrile, β-amino Amide, β-amidoamide and β-amido-α-hydroxyamide, It is possible to synthesize from saturated nitriles or from α-β-unsaturated amides. Ring closure For example, ring closure of α-bromo-β-amidocarboxylic acid to the corresponding oxazoline Mild hydrolysis followed by β-amido-α-hydroxycarboxylic acid.   According to the invention, an alkene (where R₁, R_Two, R_Three, R_FourIs hydrogen or charcoal N- (2-bromoalkyl) -amide derivative prepared from , 1,2-a It can be particularly suitably used in the preparation of mino alcohol. For this , N- (2-bromoalkyl) -amide derivatives are preferably closed under acidic conditions. It is subjected to a ring and then hydrolyzed.   The hydrolysis of the ring-closed compound to the desired 1,2-amino alcohol is preferably Performed under acidic conditions. Because in an acidic environment, these reaction steps Higher yields can be achieved than when performed in a basic environment, and in addition, 1, During the reaction to the 2-amino alcohol, it is not necessary to perform a pH change. You.   The method according to the invention is particularly preferably used for the preparation of a medicament. Taxool (t axol) (known as a therapeutic agent for tumors) is for example derived from cinnamic acid according to the invention. The use of 3-phenylisoserine prepared by the Including appropriately. The process according to the present invention comprises a process for preparing cis-1-amino-2-indanol from indene Can also be used for the preparation of Cis-1-amino-2-indanol is, for example, Preparation of medicaments, in particular for the treatment of AIDS, such as HIV-protease inhibitors Preparation, which is described, for example, in Thompson et al., J. Med. , Volume 35 , (1992), p. 1635.   Of particular interest in such applications are (2R, 1S) enantiomers. This mirror image Is derived from racemic cis-1-amino-2-indanol compound, for example, an optically active resolving agent It is easily obtained by the conventional racemic resolution used.   The terms for ring closure and hydrolysis, acidic conditions, within the scope of the present invention, It refers to a pH lower than 7, especially -3 to +3, preferably -1 to +1. like that An acidic environment can be achieved, for example, by the addition of acids, especially strong acids.   Mineral or organic acids can be used as acids. Examples of suitable acids are for the bromination reaction. Acids as described above. Preferably, strong mineral acids such as sulfuric acid, hydrochloric acid, phosphorus Acids or strong organic acids such as sulfonic acids, especially methanesulfonic acid or p-toluene Sulfonic acid is used.   The choice of solvent for ring closure and hydrolysis is not critical, for example, water or reaction A solvent that is inert under the conditions and is compatible with water in which water dissolves. Can get. Preferably, water is used. The amount of water to be used is not important, Can be determined in an easy way by the person.   The temperature at which ring closure and hydrolysis are carried out is not critical and is usually 0-120 ° C., preferably Is 40 to 105 ° C.   N- (2-bromoalkyl) -amide derivatives, formed as intermediates during hydrolysis O-acyl derivative of 1,2-aminoalcohol to be formed (the acyl group is Derived from lyl), and 1,2-aminoalcohol, if necessary. Each can be obtained separately according to known methods.   A particularly suitable method for the preparation of 1,2-aminoalcohols is N- (2- The preparation, ring closure and hydrolysis of the (bromoalkyl) -amide derivative involves, Intermediately formed Carried out without isolation of the resulting product, ie, for example, cis-1- When the conversion to amino-2-indanol is performed by a so-called one-pot reaction Is achieved. This means not only the preparation of 1,2-amino alcohol, but also the acidic environment. Ring closure and hydrolysis in is found to give high yields and good formation Found that isolation and production of intermediates was not necessary to obtain high yields of the product Is possible, which provides additional advantages. Additional benefits The point is that no change in pH (from acidic to basic environment and vice versa) is necessary. Based on the facts given, it makes it possible to realize a process with a low salt load.   The present invention will now be described with reference to, but not limited to, the following examples. You.Examples I-VII 1,3- Of dibromo-5,5-dimethylhydantoin in acetonitrile and sulfuric acid Reaction with alkenes   12.5 g of concentrated sulfuric acid was weighed into 100 ml of acetonitrile. Cool the solution to 0 ° C Was. In this solution, 0.95 g of 1,3-dibromo-5,5-dimethylhydantoin and In short, 0.006 mole of alkene was metered in. Said 1 20 weighings of alkenes to 3,3-dibromo-5,5-dimethylhydantoin Repeated. The reaction was monitored by TLC in hexane / ethyl acetate (8/2) Was.   100 ml of water was added to the reaction mixture and acetonitrile was removed under reflux. The process In, the temperature was slowly increased to 105 ° C. Continue hydrolysis at 105 ° C for 3 hours The reaction mixture was cooled to room temperature. The aqueous layer was washed with dichloromethane, a non-polar organic contaminant. Purify by extraction and aerate to pH 12 with 50% strength aqueous NaOH. Lucari. The product was obtained by dichloromethane extraction. The results are shown in the table. 1) Yield of isolated 1,2-amino alcohol (NMR-pure) 2) 19% of 1-amino-3-phenyl-2-propanol was also obtained.Example VIII   In 100 ml of acetonitrile, 0.121 mol of water was added while cooling to 0 ° C. The 0.121 mole of concentrated sulfuric acid, which had been present, was initially introduced. 0.0666 m Of 1,3-dibromo-5,5-dimethylhydantoin was suspended. Then at 0 ° C for 0.5 Over time, weigh in 0.121 mole of indene while weighing and stirring for another 0.5 hour Continued. The mixture 100 ml of water was added to the mass and acetonitrile was distilled off. The aqueous solution Refluxed for hours. After extraction with dichloromethane, the aqueous layer was washed with a 50% strength aqueous NaOH solution. To pH 12. The product was obtained by filtration. Yield 50%.Example IX   In 100 ml of acetonitrile, 0.121 mol of concentrated sulfuric acid was first added while cooling to 0 ° C. Was introduced. 0.133 mol of N-bromosuccinimide was suspended in this solution. . Then weigh in 0.121 mole of indene at 0 ° C for 0.5 hours while weighing. The stirring was continued for another 0.5 hour. 100 ml of water is added to the mixture and The nitrile was distilled off. The aqueous solution was refluxed for 3 hours. Extract with dichloromethane After that, the aqueous layer was adjusted to pH 12 with a 50% strength aqueous NaOH solution. Raw by filtration A product was obtained. Yield 50%.Example X   In 100 ml of acetonitrile, 0.121 mol of water was initially introduced. In this solution, 0.0666 mol of 1,3-dibromo-5,5-dimethylhydantoin was suspended. Then Very slowly, at 0 ° C., do not weigh 0.121 mol of indene over about 60 minutes. The mixture was weighed and the stirring was continued until the indene was completely introduced. To the mixture 100 ml of water were added and then the acetonitrile was distilled off. Allow the aqueous solution for 3 hours Refluxed. After extraction with dichloromethane, adjust the pH of the aqueous layer to 50% It was adjusted to 12 with a strong aqueous NaOH solution. The product was obtained by filtration. Yield 49 %.Example XI   In 100 ml of acetonitrile, 0.121 mol of water was added while cooling to 0 ° C. 0.121 mole of indene was initially introduced. 0.0666 m Slowly weigh in 1,3-dibromo-5,5-dimethylhydantoin Was. Then slowly meter in 0.145 moles of concentrated sulfuric acid over about 15 minutes. I weighed it. 100 ml of water are added to the mixture and then the acetonitrile is distilled off. Removed. The aqueous solution was refluxed for 3 hours. After extraction with dichloromethane, the pH of the aqueous layer Was adjusted to 12 with a 50% strength aqueous NaOH solution. The product was obtained by filtration. Income The rate is 48%.Example XII   In 100 ml of acetonitrile, 0.242 mol of water was added while cooling to 0 ° C. 0.121 moles of concentrated sulfuric acid were initially introduced. To this solution was added 0.133 mole of 1,3-Dibromo-5,5-dimethylhydantoin was suspended. Then at 0 ° C for 0.5 hour Weighed 0.242 mol of indene, and continued stirring for another 0.5 hour. Continued. 100 ml of water are added to the mixture and acetonitrile is distilled off. Was. The aqueous solution was refluxed for 3 hours. After extraction with dichloromethane, the pH of the aqueous layer was adjusted to 50 % Aqueous NaOH solution It was set to 12. The product was obtained by filtration. Yield 40%.Example XIII   65 ml of 39.3 g (0.4674 mol) of dicyandiamide and 26.0 g (0.2547 mol) of concentrated sulfuric acid The solution in formamide was cooled to 0 ° C. In the solution, alternatively 3.28 g (0.0115 mol) of DBDMH and slowly 3.0 g (0.0233 mol) of indene were measured 10 times. Weighed in while measuring. The reaction mixture was stirred at 0 ° C. for another hour. The reaction, Indene was monitored by TLC in hexane / ethyl acetate (8/2). Residual indene is further converted with an additional 2.0 g (0.007 mol) of DBDMH did. The reaction mixture is admixed with 65 ml of water and stirring is continued at 105 ° C for considerable time did. The aqueous layer was washed twice at 70 ° -90 ° C. and once at 20 ° C. with 100 ml of toluene. Extracted. The content of cis-1-amino-2-indanol in the purified aqueous layer was determined by HP Determined by LC. Calculation of cis-1-amino-2-indanol based on indene The yield value was calculated to be 48%.   Comparative example A   First, 3.40 g (0.033 mol) of concentrated sulfuric acid was introduced into 25 ml of acetonitrile at 0 ° C. did. Instead of the solution, 0.455 g (0.0016 mol) of 5,5-dibromobarbi Weigh the tool acid and 0.185 g (0.0015 mol) of indene (96%) slowly 10 times. While weighing. The reaction mixture at 20 ° C. The mixture was further stirred for 17 hours. The reaction mixture is mixed for several hours with 25 ml of water and 100 Heated to ° C. The solution was separated for cis-1-amino-2-indanol content. Was analyzed. The calculated yield value of cis-1-amino-2-indanol based on indene is It was calculated to be 3.2%.

──────────────────────────────────────────────────の Continuation of the front page (51) Int.Cl. ⁶ Identification symbol FI C07C 233/14 C07C 233/14 233/47 233/47 (72) Inventors Elsenberg, Henricus, Leonardus, Mary The Netherlands, 5931 Estee Tegelen, Agrimony 5

Claims (1)

[Claims] 1. In the presence of nitrile and water or acid, the alkene unsaturated compound is converted to positive bromine Preparation of N- (2-bromoalkyl) -amide derivatives contacted with an ion donor In the method, the positive halogen ion donor used is N-bromoimide , N-bromo selected from the group consisting of N-bromohydantoin and N-bromoamide N- (2-bromoalkyl) -amide derivatives characterized by being lomo compounds Manufacturing method. 2. The donor of the positive halogen ion used is 1,3-dibromo-5,5-dimethylhydrogen. The method according to claim 1, which is dant-in. 3. A process according to claim 1 or claim 2 wherein 3.1 to 3 acid equivalents of acid are used. 4. 4. The process according to claim 1, wherein the acid used is sulfuric acid. 5. An N- (2-bromoalkyl) -amide derivative of the chemical structural formula (1), (Where R₁And R_TwoAre independently hydrogen, alkyl, aryl, aralkyl Or a alkaryl, or a carbon atom to which they are attached Forms a ring (having 4 to 8 carbon atoms) together with an acid group, R or a amide group; R_ThreeAnd R_FourAre independently of each other hydrogen, alkyl, aryl Or aralkyl or alkaryl, or when they are bonded Form a ring (having 4 to 8 carbon atoms) with the carbon atoms of the rollers;_Five Is an alkyl group, an alkenyl group, an aryl group, an aralkyl group, an alkaryl group, (Indicating an amino group or an imino group), wherein the compound of formula (2) Alkene unsaturated compounds, (Where R₁, R_Two, R_Three, And R_FourIs defined as above) The method according to any one of items 1 to 4. 6. The resulting N- (2-bromoalkyl) -amide derivative is then subjected to a ring closure reaction A method according to any one of claims 1 to 5 provided. 7. The method according to claim 6, wherein the ring-closing compound is then subjected to hydrolysis. 8. 9. The method according to claim 6, wherein the ring closure and / or hydrolysis occurs under acidic conditions. How to follow. 9. The sequential steps are performed during which intermediate products formed are isolated. 9. A method according to any one of claims 6 to 8, which is performed without any. 10. According to chemical formula (2), R₁And / or R_TwoIs an acid group 10. A method according to claim 6, wherein an alkene unsaturated compound is used. Law. 11. According to chemical formula (2), R₁And / or R_TwoIs an amide group or a nitrile group A process according to any one of claims 6 to 9, wherein an alkene unsaturated compound is used. . 12. Cis-1-amino-2-indanol is used as an alkene unsaturated compound. 10. A method according to any one of claims 6 to 9 prepared from den. 13. Cis-1-amino-2-indanol obtained by the method according to claim 12, Optically active cis- (2R, 1S) -1-amino-characterized by being subjected to racemic compound resolution A method for producing 2-indanol. 14． The resulting N- (2-bromoalkyl) -amide derivative is then Alcohol, β-amide-α-hydroxycarboxylic acid, β-amino acid, β-amino Mimic acid, β-aminonitrile, β-amidonitrile, β-amido-α-hydroxy Sinitrile, β-aminoamide, β-amideamide or β-amide-α-hydride A method according to any one of claims 1 to 5, which is converted to roxyamide. 15. A cis-1-amino-2- obtained by the method according to claim 12 or 13. Indanol is used in the preparation of pharmaceuticals, especially in the preparation of HIV-protease inhibitors How to use.