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WO1997024357A1 - Procede de synthese et de purification d'un compose intervenant dans l'elaboration de l'acyclovir - Google Patents

Procede de synthese et de purification d'un compose intervenant dans l'elaboration de l'acyclovir Download PDF

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Publication number
WO1997024357A1
WO1997024357A1 PCT/US1996/020216 US9620216W WO9724357A1 WO 1997024357 A1 WO1997024357 A1 WO 1997024357A1 US 9620216 W US9620216 W US 9620216W WO 9724357 A1 WO9724357 A1 WO 9724357A1
Authority
WO
WIPO (PCT)
Prior art keywords
acyclovir
diacetyl
alcohol
washing
ethanol
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/US1996/020216
Other languages
English (en)
Inventor
Henry J. Buehler
Douglas C. Caskey
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.)
Mallinckrodt Chemical Inc
Original Assignee
Mallinckrodt Chemical Inc
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 Mallinckrodt Chemical Inc filed Critical Mallinckrodt Chemical Inc
Publication of WO1997024357A1 publication Critical patent/WO1997024357A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems

Definitions

  • This invention relates generally to the preparation of a purified pharmaceutical
  • Acyclovir is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N
  • acyclovir is 9-(2-hydroxyethoxymethyl)guanine
  • acyclovir obtained a highly purified, pharmaceutically acceptable acyclovir.
  • the major issue in purifying acyclovir is the removal of guanine. There are other impurities present, but
  • guanine is particularly difficult to remove because of its structural similarity to acyclovir.
  • chloropurine or 2,6-dichloropurine include purification of intermediates by column
  • silylating agent such as hexamethyldisilazane
  • DA-ACV diacetyl-acyclovir
  • DAG diacetylguanine
  • Example 44 after the alkylation is complete, the toluene solvent is decanted. The residue is triturated several times with benzene.
  • Example 45 the methanolic solution is cooled to crystallize the product, which is collected
  • Example 44 the combined methanol extracts in Example 44 employ a product concentration
  • United States Patent No. 4,544,634 also discloses a method of producing acyclovir
  • Pharmacopoeia (U.S.P XXIII standard is less than 0.7% guanine.
  • Another object of the present invention is to provide a method of synthesizing and
  • Still another object of the invention is to provide such a method of preparing
  • diacetyl-acyclovir that yields a relatively pure, crystalline form of diacetyl-acyclovir.
  • a still further object of the present invention is to provide a method of synthesizing
  • Another object of the invention is to provide a highly purified acyclovir salt
  • acyclovir is prepared by the alkylation of diacetyl guanine.
  • the diacetyl-acyclovir (DA-1) is prepared by the alkylation of diacetyl guanine.
  • ACV is converted into a novel potassium salt of acyclovir, acyclovir potassium enolate,
  • the method comprises
  • the potassium salt formed in this step is of a very high purity.
  • the invention includes the conversion of diacetyl-guanine (DAG) to a highly pure DAG (DAG)
  • DA-ACV diacetyl-acyclovir
  • the process of the present invention includes: 1) alkylation of the DAG with an
  • DA-ACV diacetyl-acyclovir
  • ACV-K purification ofthe ACV-K to form purified acyclovir (ACV).
  • the diacetyl-guanine (DAG) is commercially available and can be produced by the
  • the alkylating agent 2-oxa-l ,4-butanediol diacetate (OBD) is used to alkylate
  • DAG diacetyl-guanine
  • DA-ACV diacetyl-acyclovir
  • product wet weight is approximately 293 g.
  • the wet cake is slurried in 289.1 g (1.588 g
  • the expected weight is 203.3 g.
  • the inventors have determined that the washing of the DA-ACV is a critical step.
  • ACV product is not scrupulously dried or vigorously washed free of acetic anhydride, they will be carried forward into the hydrolysis and potassium salt formation procedure
  • the inventors have determined that when there is an elevated level of acetate- forming
  • guanine (MAG) guanine
  • MAG guanine
  • solvents were tried including methanol, ethanol, 3 A ethanol, blends of ethanol and
  • the invention also includes a reverse addition process wherein the KOH is charged
  • potassium hydroxide pellets can be done at one time by adding all of the pellets over 1 to
  • ACV Begin slow addition of a total of 148 g potassium hydroxide (KOH), 85% pellets.
  • ACV-K product acyclovir potassium enolate, with approximately 200 ml cold 3A ethanol.
  • the expected wet weight of the ACV-K salt is about 219 g. On a dry basis the expected
  • ACV-K salt is neutralized with acetic acid, treated with carbon
  • acyclovir At approximately 90°C, take a sample and check the pH. The pH
  • expected wet weight ofthe purified AVC product is approximately 220 g. Dry the product

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne des composés chimiques intermédiaires intervenant dans la préparation de l'acyclovir et un procédé de synthèse et de purification de ces composés chimiques intermédiaires. Le procédé consiste à faire l'alkylation de diacétyl-guanine et de rincer le produit résultant avec un alcool de façon à produire un diacétyl-acyclovir (DA-ACV) cristallin relativement pur. Le procédé consiste ensuite à hydrolyser le diacétyl-acyclovir (DA-ACV) en présence d'hydroxyde de potassium ce qui donne un nouveau sel de potassium de l'acyclovir, l'énolat de potassium de l'acyclovir. On convertit ensuite le sel de potassium de l'acyclovir en acyclovir sensiblement pur. Les phases d'hydrolyse du diacétyl-acyclovir et de formation du sel de potassium se produisent simultanément. On convertit ensuite le sel de potassium de l'acyclovir en acyclovir en faisant une dissolution dans l'eau en présence d'un acide de façon à produire un acyclovir sensiblement pur. L'acyclovir ainsi obtenu, qui ne nécessite normalement plus d'autre purification, respecte la recommandation USP XXIII. L'invention permet ainsi la synthèse de diacétyl-acyclovir intermédiaire purifié, la conversion du diacétyl-acyclovir en sel de potassium de l'acyclovir, et la conversion du sel de potassium de l'acyclovir en acyclovir.
PCT/US1996/020216 1995-12-28 1996-12-17 Procede de synthese et de purification d'un compose intervenant dans l'elaboration de l'acyclovir Ceased WO1997024357A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US935295P 1995-12-28 1995-12-28
US60/009,352 1995-12-28

Publications (1)

Publication Number Publication Date
WO1997024357A1 true WO1997024357A1 (fr) 1997-07-10

Family

ID=21737117

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1996/020216 Ceased WO1997024357A1 (fr) 1995-12-28 1996-12-17 Procede de synthese et de purification d'un compose intervenant dans l'elaboration de l'acyclovir

Country Status (1)

Country Link
WO (1) WO1997024357A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112300166A (zh) * 2020-10-06 2021-02-02 湖北益泰药业股份有限公司 一种母液中分离阿昔洛韦和乙酸钠的方法
CN113620955A (zh) * 2021-07-29 2021-11-09 浙江浙北药业有限公司 一种阿昔洛韦的制备方法
CN116768900A (zh) * 2023-05-06 2023-09-19 广州清瑞生物科技有限责任公司 一种用于阿昔洛韦质量控制的对照品的制备方法

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4146715A (en) * 1975-08-27 1979-03-27 Burroughs Wellcome Co. 2-amido-9-(2-acyloxyethoxymethyl)hypoxanthines
GB1567671A (en) * 1976-08-27 1980-05-21 Wellcome Found Preparation of purine compounds
EP0289992A2 (fr) * 1987-05-04 1988-11-09 Kemijski Institut Procédé pour la préparation de dérivés de purine
EP0665229A1 (fr) * 1994-02-01 1995-08-02 Ajinomoto Co., Inc. Procédé pour la production de dérivés d'une base d'acide nucléique
EP0704445A1 (fr) * 1994-08-04 1996-04-03 F. Hoffmann-La Roche AG Préparation des composés de guanine substitués sur la position 9

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4146715A (en) * 1975-08-27 1979-03-27 Burroughs Wellcome Co. 2-amido-9-(2-acyloxyethoxymethyl)hypoxanthines
GB1567671A (en) * 1976-08-27 1980-05-21 Wellcome Found Preparation of purine compounds
EP0289992A2 (fr) * 1987-05-04 1988-11-09 Kemijski Institut Procédé pour la préparation de dérivés de purine
EP0564006A2 (fr) * 1987-05-04 1993-10-06 KRKA, tovarna zdravil, n.sol.o Dérivés de purine et procédé pour leur préparation
EP0665229A1 (fr) * 1994-02-01 1995-08-02 Ajinomoto Co., Inc. Procédé pour la production de dérivés d'une base d'acide nucléique
EP0704445A1 (fr) * 1994-08-04 1996-04-03 F. Hoffmann-La Roche AG Préparation des composés de guanine substitués sur la position 9

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
AM.J. HEALTH-SYST.PHARM, vol. 52, no. 10, 1995, pages 1086 - 1090 *
AM.J. HOSP. PHARM., vol. 51, no. 4, 1994, pages 495 - 499 *
CHEMICAL ABSTRACTS, vol. 120, no. 26, 27 June 1994, Columbus, Ohio, US; abstract no. 330958n, page 496; column l; XP002025746 *
CHEMICAL ABSTRACTS, vol. 123, no. 4, 24 July 1995, Columbus, Ohio, US; abstract no. 40802c, page 516; column R; XP002025747 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112300166A (zh) * 2020-10-06 2021-02-02 湖北益泰药业股份有限公司 一种母液中分离阿昔洛韦和乙酸钠的方法
CN113620955A (zh) * 2021-07-29 2021-11-09 浙江浙北药业有限公司 一种阿昔洛韦的制备方法
CN116768900A (zh) * 2023-05-06 2023-09-19 广州清瑞生物科技有限责任公司 一种用于阿昔洛韦质量控制的对照品的制备方法

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