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WO1997017050A2 - Procede ameliore de preparation de tetrahydroisoquinoleines substituees - Google Patents

Procede ameliore de preparation de tetrahydroisoquinoleines substituees Download PDF

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Publication number
WO1997017050A2
WO1997017050A2 PCT/US1996/017926 US9617926W WO9717050A2 WO 1997017050 A2 WO1997017050 A2 WO 1997017050A2 US 9617926 W US9617926 W US 9617926W WO 9717050 A2 WO9717050 A2 WO 9717050A2
Authority
WO
WIPO (PCT)
Prior art keywords
isomer
substantially pure
formaldehyde
phenylalanine
precipitate
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.)
Ceased
Application number
PCT/US1996/017926
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English (en)
Other versions
WO1997017050A3 (fr
Inventor
Brian Griffin
Mark R. Johnson
Ronald L. Keller
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.)
Monsanto Co
Original Assignee
Monsanto Co
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 Monsanto Co filed Critical Monsanto Co
Priority to AU77244/96A priority Critical patent/AU7724496A/en
Publication of WO1997017050A2 publication Critical patent/WO1997017050A2/fr
Publication of WO1997017050A3 publication Critical patent/WO1997017050A3/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
    • C07D217/26—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen

Definitions

  • the present invention relates generally to an improved method for the preparation of a compound in a substantially optically pure fo ⁇ n. More specifically, the method relates to the stereospecific preparation and isolation of an optically pure amino acid in a single step.
  • Amino acids and peptides serve as important pharmaceutical and food additives in both human and animal diets and their production and purification have become vital to numerous food, drug and chemical industries. Many amino acids are made either chemically or through fermentation processes which require the separation and isolation of the desired amino acids from the broth.
  • L-phenylalanine for example, is a precursor or component for many pharmaceutically active peptides and food additives and it exists in both the L and D forms. In may cases, the L form of the compound may be active whereas the D-isomer is not and visa versa. Therefore it is desirable to produce only a single isomer or be able to isolate the active isomeric form.
  • phenylalanine has been resolved by the enzymatic hydrolysis of its racemic esters.
  • the enzyme, chymotrypsin selectively hydrolyzes L-phenylalanine esters.
  • L-phenylalanine is then recovered from a mixture of the D, L-phenylalanine ester.
  • An example of this process is European Patent Application EP 174,862 to E pie (8/17/84).
  • 3-carboxylic acid is an amino acid that has shown to be a useful starting material in the enzymatic and chemical synthesis of a number of pharmaceutically active peptides and peptide analogues such as the bradykinin agonists, ACE inhibitors and hypotensive drugs.
  • the D-form of the compound generally has a different activity, so a mixture of the isomer is not desirable or useful. This presents a problem in that the synthesis of the compound from phenylalanine using the Pictet-Spengler reaction results in a mixture of both isomers.
  • a method for the preparation of optically pure (3S)-1, 2, 3, 4-tetrahydroisoquinoline-3-carboxylic acid is therefore desirable.
  • tetrahydroisoquinoline derivatives are formed by the condensation of -arylethylamines with carbonyl compounds and cyclization of the Schiff bases formed. More specifically, L-phenylalanine is reacted as set forth below to produce a major product, L-TIC A (70-90%) and a minor product, D-TIC A (10-30%). See Pictet, A., Spengler, T. Ber Dtsch Chem Ges 1911, 44, 2030; and Archer, SJ. Org. Chem 1951, 16, 430. The reaction occurs as follows:
  • Racemic and optically pure 1, 2, 3, 4-tetrahydroisoquinoline-3- carboxylic acids and esters have also been prepared by the base-catalyzed cyclization reaction of 1, 2-bis(halomethyl)benzenes with dimethyl 2- (acetylamino) malonate with subsequent decarboxylation and amide cleavage Kammermaier et al. Synthesis 1157 (Nov. 1992).
  • Enantiomer resolution is achieved by esterification with menthol followed by column chromatography or by diastereomeric salt separation of the benzyl ester with mandelic acid and a base catalyzed saponification.
  • EPA 496 369 to Kammermaier discloses a method for the preparation of racemic TIC-A whereby dihalo-o-xylene is cyclized with N- acylamidomalonic acid dialkyl esters in a basic medium to dicarboxylic esters which are subsequently saponified and acidified to the final product.
  • EPA 049 658 to Remond et al. discloses the preparation of (3S)-tetrahydroisoquinoline-3-carboxylic acid through the treatment of (S) -phenylalanine with concentration hydrochloric acid and a 40% formaldehyde solution. After heating and subsequently cooling, the compound in its racemic forms crystallizes out.
  • United States Patent No. 4,847,409 to Kidman et al. discloses a method for the isolation of a substantially pure L-isomer of an amino acid from its D, L-mixture that does not require the use of a resolving agent, the formation of a derivative of the amino acid or additional enzymatic reactions.
  • the method is based on the equal saturation point whereby the L-isomer can be precipitated out and separated from the D-isomer when the relative concentration of the D-isomer is less than 7.0%.
  • 2, 3, 4-tetrahydroisoquinoIine-3-carboxylic acid or (3R)-1, 2, 3, 4- tetrahydroisoquinoline-3-carboxylic acid comprises reacting formaldehyde with D-phenylalanine or L-phenylalanine in a hydrobromic acid solution. The mixture is then filtered and washed to provide the optically pure hydrobromide salt. This may be subsequently neutralized with a base to form the optically pure free amino acid.
  • the present invention pertains to a "one-pot" method for the preparation of an optically pure (3S)-1, 2, 3, 4-tetrahydroisoquinoline-3- carboxylic acid (L-TIC-A) that does away with the multi-step processes of the prior art which generally require conversion ofthe free acid forms of the L- and D-isomers to the ester which is then purified and reconverted back to the optically pure free acid.
  • L-TIC-A optically pure optically pure
  • a formaldehyde or formaldehyde equivalent such as trioxane (CH 2 0) 3 , formalin or paraformaldehyde is reacted with phenylalanine to produce a high quality 1, 2, 3, 4 tetrathydroisoquinoline-3- carboxylic acid hydrobromide salt in yields of up to 85% with an enantiomeric excess of 99% or better, as opposed to typical yields of 689r with an e ⁇ taniomeric excess of 74% by the original method.
  • This improvement of the Pictet-Spengler method allows greater control over yield and optical purity without further derivatization of the phenethylamine substrate.
  • This simple process for the preparation of isomerically pure L-TTC-A is a practical means of purifying this "key" intermediate on a manufacturing scale and thus surprisingly and unexpectedly provides a viable supply of starting material for the synthesis of the aforementioned useful derivatives.
  • This process may be used starting from (D) phenylalanine to give pure D-TIC-A free acid by similar analogy.
  • L-phenylalanine or pure D- phenylalanine is mixed with a formaldehyde in a cyclocondensation reaction in the presence of hydrobromic acid (HBr).
  • HBr hydrobromic acid
  • the mixture is filtered to yield the optically pure TIC-A as the hydrobromide salt.
  • This method produces an optically pure reaction product comprised of greater than 97% of the L-isomer of TIC-A.
  • some racemization takes place requiring further treatment if an isomerically pure compound is to be obtained.
  • the weight percentage of L-phenylalanine can comprise from about 5.0 wt% to about 30 wt% of the total weight of the mixture. Most preferably, from about 10 wt% to about 20 wt% is used.
  • the acid of choice in the practice of the present invention is hydrogen bromide (HBr).
  • the concentration of the hydrobromic acid ranges from approximately 45% to about 65%.
  • the amount of formaldehyde may also vary but again this can be added to the reaction system on at least a 1:1 formaldehyde/phenylalaninemolar basis or in excess thereof. Preferably the formaldehyde/L-phenylalanine ratio will be less than 3:1 for best results.
  • the formaldehyde may be added to the system in equal portions for a period of 1-2 hours.
  • the reaction is run at elevated temperatures of from about 40°C to about 150°C and preferably in a range of from about 70°C to about 90°C.
  • the system is heated for a period of time of from about 6.0 to 10.0 hours at which time the solution is cooled and the TIC-A-HBr crystals precipitated.
  • the duration of time is directly related to the temperature so the greater the temperature, the shorter the time necessary.
  • the crystals are neutralized with sodium hydroxide or other bases in order to convert the TIC-A salt to the free acid form and the precipitated crystals are then washed, filtered and dried.
  • the enantiomeric excess of the product is generally greater than 99%.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

Procédé amélioré de préparation et d'isolement d'acide (3S) ou (3R)-1, 2, 3, 4-tétrahydroisoquinoléine-3-carboxylique optiquement pur. Ce procédé consiste à faire réagir du formaldéhyde avec de la phénylalanine D ou L et de l'acide hydrobromique pour obtenir des sels d'hydrobromure pur. Le mélange est ensuite refroidi pour obtenir par précipitation l'isomère optiquement pur qui est filtré puis neutralisé à l'aide d'une base pour former l'acide libre avant d'être séché.
PCT/US1996/017926 1995-11-09 1996-11-08 Procede ameliore de preparation de tetrahydroisoquinoleines substituees Ceased WO1997017050A2 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU77244/96A AU7724496A (en) 1995-11-09 1996-11-08 An improved method for preparation of substituted tetrahydroisoquinolines

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US55624995A 1995-11-09 1995-11-09
US08/556,249 1995-11-09

Publications (2)

Publication Number Publication Date
WO1997017050A2 true WO1997017050A2 (fr) 1997-05-15
WO1997017050A3 WO1997017050A3 (fr) 1997-06-05

Family

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1996/017926 Ceased WO1997017050A2 (fr) 1995-11-09 1996-11-08 Procede ameliore de preparation de tetrahydroisoquinoleines substituees

Country Status (2)

Country Link
AU (1) AU7724496A (fr)
WO (1) WO1997017050A2 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0823425A1 (fr) * 1996-07-29 1998-02-11 Archimica S.p.A. Procédé pour la préparation d'acide tétrahydroquinoléine-carboxylique optiquement pure

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5200416A (en) * 1980-05-12 1993-04-06 Usv Pharmaceutical Corporation Cyclic amides
TW224454B (fr) * 1991-01-24 1994-06-01 Hoechst Ag
US5256783A (en) * 1991-09-18 1993-10-26 Hoffmann-La Roche Inc. Method for producing 2-isoquinoline compounds
EP0578163A1 (fr) * 1992-07-09 1994-01-12 Hoechst Aktiengesellschaft Procédé de préparation de l'acide D,L ou D,L-1,2,3,4-tétrahydro-isoquinoléine-3-carboxylique

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0823425A1 (fr) * 1996-07-29 1998-02-11 Archimica S.p.A. Procédé pour la préparation d'acide tétrahydroquinoléine-carboxylique optiquement pure
US5905155A (en) * 1996-07-29 1999-05-18 Archimica Spa Process for the preparation of an optically pure tetrahydroquinoline carboxylic acid

Also Published As

Publication number Publication date
WO1997017050A3 (fr) 1997-06-05
AU7724496A (en) 1997-05-29

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