WO1998046629A1 - Appareil permettant de mettre graduellement fin a une dependance - Google Patents

Appareil permettant de mettre graduellement fin a une dependance Download PDF

Info

Publication number
WO1998046629A1
WO1998046629A1 PCT/NL1998/000189 NL9800189W WO9846629A1 WO 1998046629 A1 WO1998046629 A1 WO 1998046629A1 NL 9800189 W NL9800189 W NL 9800189W WO 9846629 A1 WO9846629 A1 WO 9846629A1
Authority
WO
WIPO (PCT)
Prior art keywords
group
hexahydroaspartame
amide
hydrogenation
hydrogenolysis
Prior art date
Application number
PCT/NL1998/000189
Other languages
English (en)
Inventor
Gerardus Karel Maria Verzijl
Quirinus Bernardus Broxterman
Original Assignee
Dsm N.V.
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 N.V. filed Critical Dsm N.V.
Priority to AU67504/98A priority Critical patent/AU6750498A/en
Publication of WO1998046629A1 publication Critical patent/WO1998046629A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06104—Dipeptides with the first amino acid being acidic
    • C07K5/06113—Asp- or Asn-amino acid
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the invention relates to hexahydroaspartame amides, of the formula 1
  • Such hexahydroaspartame amides are particularly suitable as an intermediate in the preparation of (pseudo)peptides with antithrombotic action, for example as described in US-A-5332726.
  • the preparation of (pseudo)peptides, as described in this patent, involves a complicated route via peptides being linked together.
  • the novel compounds according to the invention provide for a much simpler and less expensive. synthesis route.
  • the invention also relates to the preparation of hexahydroaspartame amides and salts thereof.
  • the fact is that it proved possible, starting from an inexpensive base material, the methyl ester of L-N-protected aspartyl-L-phenylalanine (N-protected
  • APM methyl ester of (Z-L-aspartyl) - L-phenylalanine
  • N-protecting group Possible candidates for the N-protecting group in principle include all those protective groups which can be used in peptide chemistry, for example the protective groups described in T.W. Green, Protective groups in Organic Synthesis, John Wiley & Son, New York, 1981.
  • protective groups include the t-butyloxycarbonyl group (BOC) , the formyl group, the fluorenylmethoxycarbonyl group (FMOC) , and the benzyloxycarbonyl group (Z) .
  • BOC t-butyloxycarbonyl group
  • FMOC fluorenylmethoxycarbonyl group
  • Z benzyloxycarbonyl group
  • N-protected APM preferably Z-APM
  • Z-APM is first subjected to an amidation with the aid of NH 3 to give the corresponding amide (N-protected AP-NH 2 ) . It was found that in contrast to unprotected APM, the amidation of N-protected APM can be carried out readily and with a high yield.
  • solvents can be used as the solvent in the amidation which are inert in the reaction and in which the N-protected APM, NH 3 and the ammonium salt of N-protected APM are reasonably soluble.
  • solvents often used in practice include water and alcohols.
  • the solution can be maintained under NH 3 pressure, to increase the NH 3 concentration.
  • the amidation of N-protected APM is preferentially carried out in an aqueous solution saturated with ammonia.
  • the temperature at which the amidation is carried out is not critical and is preferably between 5 and 35°C, in particular between 15 and 25°C. The most important factors in determining the temperature to be employed are the occurrence of side reactions and the effect of the temperature on the solubility of the various components present in the reaction mixture.
  • the N-protected AP-NH 2 obtained can then have its protective group removed, in a manner known in principle, and the phenyl group can be hydrogenated.
  • Z-APM-NH 2 for example, is subjected to a hydrogenation in the presence of H 2 , so that the phenyl group becomes saturated and the protective group is removed. Both reactions can be carried out simultaneously; the removal of the protective group and the saturation of the phenyl ring can alternatively be carried out in two separate steps .
  • the removal of the Z group can, in principle, involve the use of the known hydrogenolysis catalysts, for example Pt, Rh or Co, in particular Pd, possibly on a support, for example a carbon or alumina support, or Ni, possibly on a support, for example on alumina or silica. Preference is given to the use of a Pd/C, in particular 2-10 wt% Pd on C.
  • solvents can be used as the solvent which are inert in the hydrogenolysis, for example alcohols, in particular methanol; water; ketones, in particular methyl isobutyl ketone (MIBK) ; esters, in particular ethyl acetate; carboxylic acids, in particular acetic acid; and mixtures of solvents, in particular CH 3 OH/H 2 0, MIBK/H 2 0 and CH 3 OH/acetic acid.
  • carboxylic acids for example acetic acid
  • amines can be converted into salts which are more soluble in polar systems. Preference is given to the use of a methanol/water, a methanol/acetic acid or a methanol/water/acetic acid mixture.
  • the temperature at which the hydrogenolysis takes place is not particularly critical and is preferably between 20 and 100°C, in particular between 40 and 60°C.
  • the H 2 pressure at which the hydrogenolysis reaction is carried out is equally noncritical and preferably varies from atmospheric pressure to 1 MPa.
  • the hydrogenation of the phenyl ring to a cyclohexyl group can in principle involve the use of the same catalysts as with the hydrogenolysis of the Z group, for example a Pd, Raney-Ni, supported (for example on Raney-Ni Al 2 0 3 ) Ni, Rh, Ru or Pt catalyst, in particular a supported 2-10 wt% Rh, supported 2-10 wt% Pd or supported 2-10 wt% Pt catalyst, the support used preferably being carbon or alumina.
  • the solvent used can in principle be chosen from the same solvents as in the hydrogenolysis reaction.
  • the H 2 pressure at which the hydrogenation of the phenyl group is carried out is not particularly critical and varies as a function of the catalyst.
  • a pressure between atmospheric pressure and 5 MPa, in particular between atmospheric pressure and 1 MPa is used, and if an Ni or Pd catalyst is employed, a pressure between atmospheric pressure and 20 MPa is used.
  • the temperature is noncritical too, and is preferably between 25 and 100°C.
  • the pressure applied if a 2-10 wt% Pd/C catalyst is employed, preferably varies from atmospheric pressure to 10 MPa at a temperature between 20 and 100°C.
  • a RaNi or a supported Ni catalyst an H 2 pressure of between 5 and 20 MPa is preferably used at a temperature between 40 and 100 °C.
  • a combination of catalysts for example a combined Rh or Pt and Pd catalyst, preferably supported.
  • the hexahydroaspartame amide obtained can, if required, then be provided with a protective group on the amino group of the asparagine unit, use being made of standard methods which are frequently employed in peptide synthesis and are known to those skilled in the art.
  • a BOC protective group can be attached by bringing the hexahydroaspartame amide into contact with (BOC) 2 0.
  • Salts of hexahydroaspartame amides of the formula 1 are to be understood, within the scope of the present invention, as salts, for example, alkali metal salts or alkaline earth metal salts of hexahydroaspartame amides, for example Na, K, or (tetraalkyl) ammonium salts of the compounds according to formula 1 as well as acid salts of the compounds according to formula 1 where R is equal to H, for example salts of mineral acids, in particular hydrochloric acid, phosphoric acid, nitric acid or sulphuric acid.
  • the invention will be explained in more detail with reference to the examples, without being limited thereto, however.
  • the deprotecting operation was complete after 2 hours (monitored via TLC) .
  • 30 g of 41% strength hydrochloric methanol were added to the mixture.
  • the catalyst was filtered off and the solution was boiled down to a final weight of 80 g.
  • the acetic acid solution of AP-NH 2 HCl was taken up in 500 ml of 1 N HCl and hydrogenated with 10.3 g of 5% Pt/C at room temperature and 0.4 MPa of H 2 over a period of 24 h.
  • the catalyst was filtered off and washed with 150 ml of 1 N HCl.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Genetics & Genomics (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • General Health & Medical Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Peptides Or Proteins (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)

Abstract

Appareil comportant un certain nombre de boutons de commande, un afficheur, une unité centrale de traitement, une mémoire et un algorithme. Ledit appareil est portable et l'algorithme de l'appareil est conçu pour faire prendre conscience à l'utilisateur d'une dépendance et pour guider la réduction de l'utilisation par l'utilisateur de certains agents entraînant une dépendance.
PCT/NL1998/000189 1997-04-14 1998-04-03 Appareil permettant de mettre graduellement fin a une dependance WO1998046629A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU67504/98A AU6750498A (en) 1997-04-14 1998-04-03 Hexahydroaspartame amides and method for the preparation thereof

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
NL1005808 1997-04-14
NL1005808A NL1005808C2 (nl) 1997-04-14 1997-04-14 Hexahydro-aspartaamamiden en werkwijze voor de bereiding ervan.

Publications (1)

Publication Number Publication Date
WO1998046629A1 true WO1998046629A1 (fr) 1998-10-22

Family

ID=19764786

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/NL1998/000189 WO1998046629A1 (fr) 1997-04-14 1998-04-03 Appareil permettant de mettre graduellement fin a une dependance

Country Status (3)

Country Link
AU (1) AU6750498A (fr)
NL (1) NL1005808C2 (fr)
WO (1) WO1998046629A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2779431A1 (fr) * 1998-06-05 1999-12-10 Rhone Poulenc Rorer Sa Procede de preparation de l'aspartyl cyclohexylalaninamide
WO1999064443A1 (fr) * 1998-06-05 1999-12-16 Aventis Pharma S.A. Procede de preparation de l'aspartyl cyclohexylalaninamide
EP1030831A1 (fr) * 1997-10-10 2000-08-30 Aventis Pharmaceuticals Products Inc. Preparation des pseudotetrapeptides azacycloalkylalcanoyles

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0405506A1 (fr) * 1989-06-30 1991-01-02 Abbott Laboratories Ligants tétrapeptidiques du type B CCK récepteur
WO1991004746A1 (fr) * 1989-09-29 1991-04-18 Rhone-Poulenc Rorer International (Holdings) Inc. Peptides et pseudopeptides antithrombotiques
US5332726A (en) * 1989-09-29 1994-07-26 Rhone-Poulenc Rorer Pharmaceuticals Inc. Antithrombotic peptides and pseudopeptides

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0405506A1 (fr) * 1989-06-30 1991-01-02 Abbott Laboratories Ligants tétrapeptidiques du type B CCK récepteur
WO1991004746A1 (fr) * 1989-09-29 1991-04-18 Rhone-Poulenc Rorer International (Holdings) Inc. Peptides et pseudopeptides antithrombotiques
US5332726A (en) * 1989-09-29 1994-07-26 Rhone-Poulenc Rorer Pharmaceuticals Inc. Antithrombotic peptides and pseudopeptides

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1030831A1 (fr) * 1997-10-10 2000-08-30 Aventis Pharmaceuticals Products Inc. Preparation des pseudotetrapeptides azacycloalkylalcanoyles
EP1030831A4 (fr) * 1997-10-10 2003-01-02 Aventis Pharm Prod Inc Preparation des pseudotetrapeptides azacycloalkylalcanoyles
FR2779431A1 (fr) * 1998-06-05 1999-12-10 Rhone Poulenc Rorer Sa Procede de preparation de l'aspartyl cyclohexylalaninamide
WO1999064443A1 (fr) * 1998-06-05 1999-12-16 Aventis Pharma S.A. Procede de preparation de l'aspartyl cyclohexylalaninamide
US6384272B2 (en) 1998-06-05 2002-05-07 Aventis Pharma S.A. Method for preparing aspartylcyclohexyla laninamide

Also Published As

Publication number Publication date
AU6750498A (en) 1998-11-11
NL1005808C2 (nl) 1998-10-19

Similar Documents

Publication Publication Date Title
PL191750B1 (pl) Sposób oczyszczania estru 1-metylowego N-[N-(3,3-dimetylobutylo)-L- α-aspartylo]-L-fenyloalaniny oraz sposób wytwarzania estru 1-metylowego N-[N-(3,3-dimetylobutylo)-L- α-aspartylo]-L-fenyloalaniny
CA2006560A1 (fr) Procede de preparation de retro-inversopeptides et nouveaux intermediaires
CA2383184A1 (fr) Procede de preparation de h-tyr-d-ala-phe(f)-phe-nh2
JPH0357118B2 (fr)
WO1998046629A1 (fr) Appareil permettant de mettre graduellement fin a une dependance
US5712367A (en) Process for the solubilization of peptides and process for peptide synthesis
HU208838B (en) Method for producing peptones containing aza aminoacides by means of solid-phase synthesis
JPH07300450A (ja) グアニジンの製造方法
JPH08119916A (ja) Ｎ−保護グルタミン酸γ−誘導体の選択的製造法
JP2662287B2 (ja) α―Ｌ―アスパルチル―Ｌ―フェニルアラニンメチルエステルの分離方法
JPH1045692A (ja) シクロヘキシルアミノ酸類の製造方法
WO1999047548A1 (fr) Procede de preparation d'un tetrapeptide
CA2421550C (fr) Procede de preparation de midodrine, sels pharmaceutiquement acceptables a base de midodrine et intermediaires
WO1992009620A1 (fr) Procede pour synthetiser en phase de solution un peptide
WO2004037772A1 (fr) Synthese pratique et modifiable de l'ethyl n-[(2-boc-amino) ethyl] glycinate et de son chlorhydrate
CN114805477B (zh) L-赖氨酰-l-酪氨酸合成方法
CN109734627A (zh) 一种新的化合物n-2-烷酰基-n-6-芴甲氧羰基-l-赖氨酸
WO2000039071A1 (fr) Procede de production de l-erythro-(1r, 2s)-2-amino-1-phenylpropan-1-ol
JP2748897B2 (ja) 新規なアルギニン誘導体およびこれを用いるペプチドの製造方法
JP3902121B2 (ja) ４，６−ジメチルインドールの製造方法
JP2688210B2 (ja) Ｎ−保護アスパラギン酸無水物の製造法
Warshawsky et al. Ring cleavage of N-acyl-and N-(arylsulfonyl) histamines with Di-tert-butyl dicarbonate. A one-pot synthesis of 4-acylamino-and 4-arylsulfonylamino-1, 2-diaminobutanes
JP2698372B2 (ja) Ｎ−保護アスパラギン酸無水物の製造方法
JP2880744B2 (ja) α―Ｌ―アスパルチル―Ｌ―フェニルアラニンエステルの製造法
KR970002910B1 (ko) 촉매환원 방법에 의한 아스파탐의 제조방법

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AL AU BA BB BG BR CA CN CU CZ EE GE HU ID IL IS JP KP KR LC LK LR LT LV MG MK MN MX NO NZ PL RO SG SI SK SL TR TT UA US UZ VN YU

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): GH GM KE LS MW SD SZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN ML MR NE SN TD TG

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
121 Ep: the epo has been informed by wipo that ep was designated in this application
NENP Non-entry into the national phase

Ref country code: JP

Ref document number: 1998543761

Format of ref document f/p: F

122 Ep: pct application non-entry in european phase
NENP Non-entry into the national phase

Ref country code: CA