EP0832059A1 - Verfahren zur herstellung von n-(2-bromoalkyl)-amide-derivate - Google Patents

Verfahren zur herstellung von n-(2-bromoalkyl)-amide-derivate

Info

Publication number
EP0832059A1
EP0832059A1 EP96917728A EP96917728A EP0832059A1 EP 0832059 A1 EP0832059 A1 EP 0832059A1 EP 96917728 A EP96917728 A EP 96917728A EP 96917728 A EP96917728 A EP 96917728A EP 0832059 A1 EP0832059 A1 EP 0832059A1
Authority
EP
European Patent Office
Prior art keywords
acid
amido
group
preparation
bromoalkyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP96917728A
Other languages
English (en)
French (fr)
Inventor
Gerardus Karel Maria Verzijl
Quirinus Bernardus Broxterman
Henricus Leonardus Marie Elsenberg
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Koninklijke DSM NV
Original Assignee
DSM NV
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by DSM NV filed Critical DSM NV
Publication of EP0832059A1 publication Critical patent/EP0832059A1/de
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/06—Preparation of carboxylic acid amides from nitriles by transformation of cyano groups into carboxamide groups
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
    • C07C2602/08—One of the condensed rings being a six-membered aromatic ring the other ring being five-membered, e.g. indane

Definitions

  • 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.
  • the object of the invention is a method wherein the desired N-(2-bromoalkyl)-amido derivative is obtained in a relatively high yield.
  • N-bromo compound from the group consisting of N-bromoimides, N- bromohydantoins and N-bromoamides.
  • N-bromo compounds which can be prepared by means of the method according to the invention can be represented by the general formula (1)
  • R x , R 2 , R 3 , R 4 and R 5 in this formula is not particularly critical.
  • R x , R 2 , R 3 and R 4 are defined by the choice of the alkenically unsaturated compound, within the scope of this invention sometimes simply referred to as alkene,
  • R x and/or R 2 may represent an acid group, a nitrile or an amide.
  • R 5 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 R 5 .
  • the nitrile chosen is usually R 5 -C ⁇ N, but other compounds which, after the bromination reaction, afford the desired R 5 -amido substituent can also be employed.
  • 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 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.
  • 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.
  • 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.
  • sulphuric 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.
  • 1-3 acid equivalents of acid are used.
  • 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.
  • 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 ⁇ -(2-bromoalkyl)-amido derivative prepared according to the invention can, for example, be used in the preparation of ⁇ -amido acids, ⁇ -amino acids and ⁇ -amido- ⁇ -hydroxycarboxylic acids.
  • an ⁇ - ⁇ -unsaturated acid as the alkenically unsaturated compound, is first converted, by means of the method according to the invention, into an ⁇ -bromo- ⁇ -amido acid, followed by a reduction to the ⁇ -amido acid; hydrolysis of the ⁇ -amido acid subsequently affords the corresponding ⁇ -amino acid.
  • An ⁇ -(2-bromoalkyl)-amido derivative prepared according to the invention from an alkene wherein R lf R 2 , R 3 , R 4 represent H or a hydrocarbon group, can be employed particularly suitably in the preparation of 1,2-aminoalcohols.
  • 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 .
  • 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.
  • suitable acids are the acids as described above within the scope of the bromination reaction.
  • 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.
  • 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% .
  • 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 H 2 S0 4 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.
  • 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%.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Communicable Diseases (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Virology (AREA)
  • Oncology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
EP96917728A 1995-06-14 1996-06-13 Verfahren zur herstellung von n-(2-bromoalkyl)-amide-derivate Withdrawn EP0832059A1 (de)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
BE9500528A BE1009427A3 (nl) 1995-06-14 1995-06-14 Werkwijze voor de bereiding van cis-1-amino-2-indanol uit een trans-1-amido-2-haloindaanverbinding, trans-1-amino-2-haloindaanverbindingen en werkwijze voor de bereiding van trans-1-amido-2-haloindaanverbindingen.
BE9500528 1995-06-14
PCT/NL1996/000237 WO1997000237A1 (en) 1995-06-14 1996-06-13 Process for the preparation of an n-(2-bromoalkyl)-amide derivate_______________________________________________________________

Publications (1)

Publication Number Publication Date
EP0832059A1 true EP0832059A1 (de) 1998-04-01

Family

ID=3889037

Family Applications (1)

Application Number Title Priority Date Filing Date
EP96917728A Withdrawn EP0832059A1 (de) 1995-06-14 1996-06-13 Verfahren zur herstellung von n-(2-bromoalkyl)-amide-derivate

Country Status (4)

Country Link
EP (1) EP0832059A1 (de)
JP (1) JPH11507665A (de)
BE (1) BE1009427A3 (de)
WO (1) WO1997000237A1 (de)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP6014512B2 (ja) * 2013-02-19 2016-10-25 国立大学法人東京工業大学 トリフルオロメチル基含有アミノ化合物の製造方法

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE69417526T2 (de) * 1993-12-01 1999-09-09 Ichikawa Gosei Chemical Co. Ltd. Verfahren zur Herstellung von cis-1-Aminoindan-2-ol

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9700237A1 *

Also Published As

Publication number Publication date
BE1009427A3 (nl) 1997-03-04
JPH11507665A (ja) 1999-07-06
WO1997000237A1 (en) 1997-01-03

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