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WO2009027998A2 - Procédé amélioré de préparation d'alanine-nca - Google Patents

Procédé amélioré de préparation d'alanine-nca Download PDF

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Publication number
WO2009027998A2
WO2009027998A2 PCT/IN2008/000540 IN2008000540W WO2009027998A2 WO 2009027998 A2 WO2009027998 A2 WO 2009027998A2 IN 2008000540 W IN2008000540 W IN 2008000540W WO 2009027998 A2 WO2009027998 A2 WO 2009027998A2
Authority
WO
WIPO (PCT)
Prior art keywords
alanine
nca
preparation
triphosgene
reaction
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/IN2008/000540
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English (en)
Other versions
WO2009027998A3 (fr
Inventor
Satyanarayana Kota
Venkateswarlu Tallapaneni
Bhujanga Rao Adibhatla Kali Satya
Nannapaneni Venkaiah Chowdary
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.)
Natco Pharma Ltd
Original Assignee
Natco Pharma Ltd
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 Natco Pharma Ltd filed Critical Natco Pharma Ltd
Publication of WO2009027998A2 publication Critical patent/WO2009027998A2/fr
Publication of WO2009027998A3 publication Critical patent/WO2009027998A3/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
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D263/34—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members 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 ring carbon atoms
    • C07D263/44—Two oxygen atoms

Definitions

  • Alanine-N-Carboxy anhydride (Alanine-NCA, I) is one of the four amino acid building blocks used in the preparation of glatiramer acetate.
  • the present invention describes a process for preparation of alanine-NCA by industrially convenient, environmentally friendly and safe process involving the reaction of triphosgene and alanine.
  • Alanine-NCA obtained by this process is > 99.0% pure with ⁇ 0.01% chloride content and substantially free from alanine impurity.
  • Glatiramer acetate is a synthetic peptide polymer used in the treatment of relapsing multiple sclerosis. (M. M. Mouradain, Pharmacology & Therapeutics, 98, 245-255, 2003). It is a random polymer of L-alanine, L-tyrosine, L-Glutamic acid, L-lysine and is prepared by polymerization N-Carboxy anhydrides (NCAs) of L-Tyrosine, L-alanine, L- ⁇ -benzyl L-glutamic acid and L- ⁇ -trifmoroacetyl lysine.
  • NCAs N-Carboxy anhydrides
  • NCAs which are to be >99% pure and chloride content 0.01% and free amino acid content ⁇ 0.01 %.
  • Amino acid N-carboxyanhydrides (amino acid -NCAs) are chemically 3-substituted oxazolin-2, 5-diones. Leuchs first prepared NCAs in 1906 via intermolecular cyclization of N-alkyl or N-aryloxycarbonyl amino acid halides.
  • Leuchs anhydrides (Leuchs H., Chem. Ber., 41, 1721, 1906). This method involves preparation of alkoxy aryl carbamates, conversion to acid halides, and thermally induced cyclization. This method is obsolete and of historical interest only. Amino acid -NCAs are highly unstable at room temperature and needs to be stored around -20 0 C.
  • diphosgene and triphosgene are generally used substitutes.
  • Diphosgene (trichlomethylchloroformate, TCF) is high boiling (127-128° C for TCF, versus 8.2 0 C for phosgene) hence easy to handle and is less toxic than phosgene.
  • Some amino acid NCAs were prepared using diphosgene at a small scale by reacting amino acid with diphosgene (Katakai R., Iizuka Y., J. Org. Chem., 50, 715-716, 1985). However, diphosgene is not available in quantities required at industrial scale.
  • Triphosgene (bistrichloromethyl carbonate) is crystalline compound and is less hazardous than phosgene and diphosgene.
  • Alanine -NCA was prepared using phosgene (Astbury, W.T., Dalgliesh, C.E., Darmon, S.E., Sutherland, G.B.B.M., Nature, 162, 596,1948; Hirschmann et al., J. Am. Chem. Soc. 93, 2746-2754, 1971;Bailey.J.L., J. Chem. Soc. 3461-3466; Lindberg. Et al., J. Med. Chem. Vol. 21, 448-456, 1978; Thomas J. Blacklock et al., J. Org. Chem. 53, 836-844, 1988.).
  • alanine-NCA prepared using triphosgene having >99.0% assay, ⁇ 0.01% chloride content and free from alanine.
  • Present invention describes a commercial process for preparation of tyrosine-NCA from alanine (IV) and triphosgene (V) that is economically viable, robust, and scalable linearly without using toxic phosgene gas as shown in the scheme 2.
  • the critical parameter is content of moisture in the solvent.
  • Solvents such as ethyl acetate, dioxane, tetrahydrofuran, and acetonitrile are used with moisture content less than 0.01%.
  • solvents are dried using desiccants such as calcium chloride, molecular sieves for overnight, and then double distilled, checked for moisture content. Solvents with moisture content less than 0.01% are only used in the process.
  • the particle size of alanine plays critical role in the preparation of alanine- NCA. When the commercial alanine with an average particle size of about 50 microns is used, the yield of alanine-NCA was about 50%. However, when the particle size of alanine is reduced to less than 200 microns, the rate of reaction is faster and the yield increased to > 80%. The product purity is more 95% also.
  • the reaction is conducted in presence of inert atmosphere.
  • the inert atmosphere is created by nitrogen or argon, preferable by nitrogen gas.
  • the reaction of triphosgene with alanine liberates hydrogen chloride, this react with free alanine to give alanine hydrochloride.
  • the formation of hydrochloride salt hinders progress of reaction and invariable results in alanine- NCA having chloride impurities.
  • the scrubber neutralizes liberated toxic gases.
  • the reservoir of the scrubber is filled with alkalis such as ammonia, alkali metal hydroxides.
  • triphosgene Mode of addition of triphosgene is critical to achieve highly pure alanine-NCA.
  • the reaction is incomplete.
  • triphosgene is added in the lots.
  • handling triphosgene in the lots is not convenient.
  • a solution of triphosgene is in the solvent of reaction is made and added in lots.
  • the main objective of the present invention is to provide an improved process for the preparation of alanine-NCA of formula I possessing very high purity.
  • Another objective of the present invention is to provide an improved process for the preparation of alanine-NCA possessing very high purity, with >99.0% assay, chlorides content ⁇ 0.01% and free alanine content 0.01%.
  • Still another objective of the present invention is to provide an improved process for the preparation of alanine-NCA possessing very high purity, with >99.0% assay, chlorides content ⁇ 0.01% and free alanine content 0.01% suitable for preparation of glatiramer acetate.
  • Still another objective of the present invention is to provide an improved process for the preparation alanine-NCA possessing very high purity, with >99.0% assay, chlorides content ⁇ 0.01% and free alanine content 0.01% suitable for preparation of glatiramer acetate meeting quality specifications for average molecular weight and amino acid analysis.
  • the present invention describes a process for preparation of highly pure alanine-NCA suitable for preparation of glatiramer acetate.
  • the invention involves reaction of purified alanine with triphosgene, wherein triphosgene is added in lots as solution in purified solvent.
  • Alanine-NCA obtained by this process is >99.0% pure and contains ⁇ 0.01% chlorides and free alanine.
  • ethyl acetate 37L, MC ⁇ 0.01%
  • powdered and vacuum dried alanine 500g,particle size ⁇ 200 micron, MC ⁇ 0.01%
  • the out let of reactor is connected to a scrubber.
  • the reservoir of the scrubber is filled with 10% sodium hydroxide solution and inert atmosphere is created by applying nitrogen.
  • Triphosgene 500g is dissolved in ethyl acetate (5L) and charged into the addition tank. Reaction mixture is heated to 70-80 0 C, and then triphosgene solution is added in portions during 4- 6h. After the addition of about 4.2L triphosgene solution, the reaction is clear solution.
  • Powdered and vacuum dried alanine (1Og, particle size ⁇ 200 micron, MC ⁇ 0.01%) is added to tetrahydrofuran (50OmL, MC ⁇ 0.1) and heated to reflux temperature.
  • a solution of triphosgene (1Og) in tetrahydrofuran is added during course of 6h. Reaction mixture is heated till clear solution is obtained, filtered and solvent distilled to obtain a concentrate.
  • alanine (1Og, particle size ⁇ 200 micron, MC ⁇ 0.01%) is added to acetonitrile (50OmL, MC ⁇ 0.1) and heated to reflux temperature.
  • a solution of triphosgene (1Og) in acetonitrile is added during course of 4h. Reaction mixture is heated a till clear solution is obtained, filtered and solvent distilled to obtain a concentrate.
  • hexane 500 mL, MCO.1%
  • the process is suitable for a commercial preparation. 3.
  • the process produces alanine-NCA of purity of > 99%, chlorides ⁇ 0.01% and free alanine ⁇ 0.01%.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)

Abstract

L'alanine-N-carboxy anhydride (tyrosine-NCA, I) est l'un des quatre éléments structuraux des acides aminés utilisés dans la préparation de l'acétate de glatiramère. L'invention concerne un procédé de préparation de l'alanine-NCA selon une technique industrielle commode, soucieuse de l'environnement et sûre qui fait intervenir une réaction triphosgène/tyrosine. Le produit résultant est pur à plus de 99 % et sa teneur en chlorure est inférieure à 0,01 %, et enfin il est sensiblement dépourvu d'impuretés de tyrosine.
PCT/IN2008/000540 2007-08-27 2008-08-26 Procédé amélioré de préparation d'alanine-nca Ceased WO2009027998A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN1916CH2007 2007-08-27
IN1916/CHE/2007 2007-08-27

Publications (2)

Publication Number Publication Date
WO2009027998A2 true WO2009027998A2 (fr) 2009-03-05
WO2009027998A3 WO2009027998A3 (fr) 2009-04-16

Family

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IN2008/000540 Ceased WO2009027998A2 (fr) 2007-08-27 2008-08-26 Procédé amélioré de préparation d'alanine-nca

Country Status (1)

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WO (1) WO2009027998A2 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114634547A (zh) * 2022-04-26 2022-06-17 山东济肽生物科技有限公司 一种二肽-2的合成工艺

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050276783A1 (en) * 2004-06-10 2005-12-15 Ernest Giralt Lledo Polypeptides with the capacity to entrap drugs and release them in a controlled way

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114634547A (zh) * 2022-04-26 2022-06-17 山东济肽生物科技有限公司 一种二肽-2的合成工艺

Also Published As

Publication number Publication date
WO2009027998A3 (fr) 2009-04-16

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