WO2010080969A1 - Process for the synthesis of beta glycerol phosphate - Google Patents

Process for the synthesis of beta glycerol phosphate Download PDF

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Publication number
WO2010080969A1
WO2010080969A1 PCT/US2010/020456 US2010020456W WO2010080969A1 WO 2010080969 A1 WO2010080969 A1 WO 2010080969A1 US 2010020456 W US2010020456 W US 2010020456W WO 2010080969 A1 WO2010080969 A1 WO 2010080969A1
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WO
WIPO (PCT)
Prior art keywords
compound
formula
group
reaction mixture
hydrocarbon solvent
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/US2010/020456
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English (en)
French (fr)
Inventor
Yashwant Kulkarni
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.)
Sigma Aldrich Co LLC
Original Assignee
Sigma Aldrich Co LLC
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 Sigma Aldrich Co LLC filed Critical Sigma Aldrich Co LLC
Priority to US13/142,552 priority Critical patent/US8420848B2/en
Priority to JP2011545446A priority patent/JP5639599B2/ja
Priority to CN2010800044300A priority patent/CN102272080A/zh
Priority to EP10729547.9A priority patent/EP2389348B1/en
Priority to ES10729547.9T priority patent/ES2657240T3/es
Publication of WO2010080969A1 publication Critical patent/WO2010080969A1/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/06—Phosphorus compounds without P—C bonds
    • C07F9/08—Esters of oxyacids of phosphorus
    • C07F9/09—Esters of phosphoric acids
    • C07F9/091—Esters of phosphoric acids with hydroxyalkyl compounds with further substituents on alkyl

Definitions

  • the present invention provides a method of production for highly pure beta glycerol phosphate from the corresponding glycerol or protected glycerol compounds.
  • the present invention encompasses a process for the preparation of a compound comprising Formula (Vl).
  • the process comprises (a) contacting a compound comprising Formula (I) with a protecting agent comprising R p to form a compound comprising Formula (II); (b) contacting the compound comprising Formula (II) with a phosphorylating agent comprising Z in the presence of a proton acceptor to form a compound comprising Formula (III); (c) contacting the compound comprising Formula (III) with water to form a compound comprising Formula (IV) and HZ; (d) contacting the compound comprising Formula (IV) with a proton acceptor comprising at least one metal ion (M) to form a compound comprising Formula (V); and (e) deprotecting the compound comprising Formula (V) to form the compound comprising Formula (Vl) according to the following reaction scheme:
  • R p is a protecting group
  • Z is halogen
  • M is selected from the group consisting of Group IA, Group MA, and transition metal ions.
  • Yet another aspect of the present invention comprises a process for the preparation of a compound comprising Formula (Vl).
  • the process comprises (a) contacting a compound comprising Formula (II) with a phosphorylating agent comprising Z in the presence of a proton acceptor to form a compound comprising Formula (III); (b) contacting the compound comprising Formula (III) with water to form a compound comprising Formula (IV) and HZ; (c) contacting the compound comprising Formula (IV) with a proton acceptor comprising at least one metal ion (M) to form a compound comprising Formula (V); and (d) deprotecting the compound comprising Formula (V) to form the compound comprising Formula (Vl) according to the following reaction scheme:
  • the present invention provides an efficient process for the production of beta glycerol phosphate and salts thereof of high purity.
  • the beta glycerol phosphate and salts thereof (such as, e.g., glycerol 2-phosphate disodium salt hydrate) product generally comprises greater than about 99% by weight of the ⁇ -isomer of the compound.
  • the process also prevents the formation of impurities and/or efficiently removes impurities during the course of the process.
  • One aspect of the present invention provides a method for the synthesis of beta glycerol phosphate or salts thereof [i.e., a compound comprising Formula (Vl)] using glycerol as the starting material.
  • Reaction Scheme 1 depicts the production of the compound comprising Formula (Vl) from a compound comprising Formula (I) in accordance with this aspect of the invention:
  • STEP A STEP B: Protect ng Agent Phosphorylating Agent Proton Acceptor
  • R p is a protecting group
  • Z is halogen
  • protecting group denotes a group capable of protecting an oxygen atom, wherein the protecting group, subsequent to the reaction for which protection is employed, may be removed without disturbing the remainder of the molecule.
  • suitable protecting groups include acyls (e.g., pivaloyl (i.e., 2,2-dimethyl propanoyl), adamantanoyl, methanoyl, ethanoyl (i.e., acetyl), propanoyl, butanoyl, pentanoyl, and the like); benzyls and substituted benzyls (e.g., benzyloxy, mesitoyl, and so forth); ethers (e.g., allyl, thphenylmethyl (trityl or Tr), p-methoxybenzyl (PMB), p-methoxyphenyl (PMP), and the like); acetals (e.g.,
  • organic solvents that may be employed, include, for example, acetonithle, benzene, butyl acetate, f-butyl methylether, f-butyl methylketone, chlorobenzene, chloroform, chloromethane, cyclohexane, dichloromethane, dichloroethane, diethyl ether, ethyl acetate, diethylene glycol, fluorobenzene, heptane, hexane, isobutylmethylketone, isopropyl acetate, methylethyl ketone, methyltetrahydrofuran, pentyl acetate, n-propyl acetate, tetrahydrofuran, toluene, and combinations thereof.
  • the organic solvent is f-butyl methylether.
  • the production of highly pure BGP is dependent upon minimizing the amount of the alpha isomer of the diprotected compound. This is accomplished by ensuring the compound comprising Formula (II) is predominantly composed of the beta isomer (i.e., 1 ,3-diprotected compound), rather than the alpha isomer (i.e., 1 ,2-diprotected compound). In general, high levels of the beta isomer help prevent the formation of impurities downstream and lessen the need to perform additional purifications leading to increased costs and decreased efficiency. Generally, the alpha isomer of the diprotected compound comprises less than about 20% by weight of compound comprising Formula (II).
  • R is a lower alkyl or substituted alkyl group; a lower alkenyl or substituted alkenyl group; or an aryl or substituted aryl group.
  • the reaction further comprises an oxidation step. Those of skill in the art are familiar with suitable oxidizing agents.
  • Step B is generally conducted in the presence of a proton acceptor.
  • Step B generally proceeds in the presence of an organic solvent.
  • the temperature may range from about 20 ° C to about 35 ° C.
  • ensuring that the reaction mixture does not exceed a certain temperature helps prevent the formation of impurities.
  • the non-polar hydrocarbon may include, but is not limited to alkane and substituted alkane solvents (including cycloalkanes), aromatic hydrocarbons, esters, ethers, ketones, combinations thereof, and the like.
  • Specific non-polar hydrocarbon solvents that may be employed include, for example, benzene, butyl acetate, f-butyl methylether, f-butyl methylketone, chlorobenzene, chloroform, chloromethane, cyclohexane, dichloromethane, dichloroethane, diethyl ether, ethyl acetate, diethylene glycol, fluorobenzene, heptane, hexane, isobutylmethylketone, isopropyl acetate, methylethyl ketone, methyltetrahydrofuran, pentyl acetate, n-propyl acetate, tetrahydrofuran, toluen
  • Step D can and will vary.
  • the proton acceptor is added to the reaction mixture to raise the pH of the reaction mixture.
  • the pH of the reaction mixture in Step D may be greater than about 9.
  • the pH of the reaction mixture in Step D may be greater than about 11.
  • the pH of the reaction mixture may range from about 11 to about 12.
  • the concentration of the proton acceptor generally may range from about 20% to about 80% (w/v). In a preferred embodiment, the concentration of the proton acceptor may range from about 40% to about 60% (w/v).

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Biochemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Molecular Biology (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
PCT/US2010/020456 2009-01-09 2010-01-08 Process for the synthesis of beta glycerol phosphate Ceased WO2010080969A1 (en)

Priority Applications (5)

Application Number Priority Date Filing Date Title
US13/142,552 US8420848B2 (en) 2009-01-09 2010-01-08 Process for the synthesis of beta glycerol phosphate
JP2011545446A JP5639599B2 (ja) 2009-01-09 2010-01-08 β−グリセロールリン酸を合成するためのプロセス
CN2010800044300A CN102272080A (zh) 2009-01-09 2010-01-08 β磷酸甘油的合成方法
EP10729547.9A EP2389348B1 (en) 2009-01-09 2010-01-08 Process for the synthesis of beta glycerol phosphate
ES10729547.9T ES2657240T3 (es) 2009-01-09 2010-01-08 Procedimiento de síntesis de beta glicerol fosfato

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US14356609P 2009-01-09 2009-01-09
US61/143,566 2009-01-09

Publications (1)

Publication Number Publication Date
WO2010080969A1 true WO2010080969A1 (en) 2010-07-15

Family

ID=42316823

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2010/020456 Ceased WO2010080969A1 (en) 2009-01-09 2010-01-08 Process for the synthesis of beta glycerol phosphate

Country Status (6)

Country Link
US (1) US8420848B2 (enExample)
EP (1) EP2389348B1 (enExample)
JP (1) JP5639599B2 (enExample)
CN (1) CN102272080A (enExample)
ES (1) ES2657240T3 (enExample)
WO (1) WO2010080969A1 (enExample)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8420848B2 (en) 2009-01-09 2013-04-16 Sigma-Aldrich Co. Llc Process for the synthesis of beta glycerol phosphate
CN105732700A (zh) * 2016-03-23 2016-07-06 江苏诚信药业有限公司 一种制备β-甘油磷酸钠的方法

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104163827A (zh) * 2014-05-21 2014-11-26 江苏德峰药业有限公司 一种β-磷酸甘油钠的合成方法
US20220395516A1 (en) * 2021-05-27 2022-12-15 Baxter International Inc. Pharmaceutical compositions for clinical nutrition

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3264378A (en) * 1962-04-09 1966-08-02 Armour Pharma Serine ester of diacyl glycerol phosphate
US4463095A (en) * 1982-11-26 1984-07-31 Toyo Boseki Kabushiki Kaisha Process for producing α-glycerophosphate oxidase
US4916249A (en) * 1985-07-03 1990-04-10 Hans Brachwitz Glycero-3(2)-phospho-L-serine derivatives and salts thereof
US20050050594A1 (en) * 1999-02-05 2005-03-03 Shirley Rodaway Tryptophan synthase as a site of herbicide action
US6872712B1 (en) * 1999-03-25 2005-03-29 Yeda Research And Development Co. Ltd. Cyclic glycerophosphates and analogs thereof
US6914056B1 (en) * 1999-03-25 2005-07-05 Yeda Research And Development Co., Ltd. Pharmaceutical compositions comprising cyclic glycerophosphates and analogs thereof for promoting neural cell differentiation

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3239817A1 (de) * 1982-07-06 1984-01-12 Max Planck Gesellschaft zur Förderung der Wissenschaften e.V., 3400 Göttingen Neue glycerinderivate zur synthese von phospholipiden
WO2010080969A1 (en) 2009-01-09 2010-07-15 Sigma-Aldrich Co. Process for the synthesis of beta glycerol phosphate

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3264378A (en) * 1962-04-09 1966-08-02 Armour Pharma Serine ester of diacyl glycerol phosphate
US4463095A (en) * 1982-11-26 1984-07-31 Toyo Boseki Kabushiki Kaisha Process for producing α-glycerophosphate oxidase
US4916249A (en) * 1985-07-03 1990-04-10 Hans Brachwitz Glycero-3(2)-phospho-L-serine derivatives and salts thereof
US20050050594A1 (en) * 1999-02-05 2005-03-03 Shirley Rodaway Tryptophan synthase as a site of herbicide action
US6872712B1 (en) * 1999-03-25 2005-03-29 Yeda Research And Development Co. Ltd. Cyclic glycerophosphates and analogs thereof
US6914056B1 (en) * 1999-03-25 2005-07-05 Yeda Research And Development Co., Ltd. Pharmaceutical compositions comprising cyclic glycerophosphates and analogs thereof for promoting neural cell differentiation

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
HAFTENDORN, R ET AL.: "Synthesis of 2-Modified 1,3-Diacylglycerols", TETRAHEDRON, 1995, pages 1177 - 1186, XP004104983, DOI: doi:10.1016/0040-4020(94)01013-P
See also references of EP2389348A4
T.W. GREENE; P.G.M. WUTS: "Protective Groups in Organic Synthesis", 1999, JOHN WILEY & SONS

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8420848B2 (en) 2009-01-09 2013-04-16 Sigma-Aldrich Co. Llc Process for the synthesis of beta glycerol phosphate
CN105732700A (zh) * 2016-03-23 2016-07-06 江苏诚信药业有限公司 一种制备β-甘油磷酸钠的方法

Also Published As

Publication number Publication date
CN102272080A (zh) 2011-12-07
ES2657240T3 (es) 2018-03-02
JP2012514647A (ja) 2012-06-28
US8420848B2 (en) 2013-04-16
JP5639599B2 (ja) 2014-12-10
EP2389348B1 (en) 2017-11-15
EP2389348A4 (en) 2012-09-05
EP2389348A1 (en) 2011-11-30
US20120041222A1 (en) 2012-02-16

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