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WO2012018235A2 - Procédé de préparation de décitabine assurant un meilleur rendement et une plus grande pureté - Google Patents

Procédé de préparation de décitabine assurant un meilleur rendement et une plus grande pureté Download PDF

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Publication number
WO2012018235A2
WO2012018235A2 PCT/KR2011/005724 KR2011005724W WO2012018235A2 WO 2012018235 A2 WO2012018235 A2 WO 2012018235A2 KR 2011005724 W KR2011005724 W KR 2011005724W WO 2012018235 A2 WO2012018235 A2 WO 2012018235A2
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WO
WIPO (PCT)
Prior art keywords
formula
decitabine
solvent
purity
dioxyribose
Prior art date
Application number
PCT/KR2011/005724
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English (en)
Korean (ko)
Other versions
WO2012018235A3 (fr
Inventor
김광일
오상봉
Original Assignee
케이피엑스 라이프사이언스 주식회사
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.)
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Publication date
Application filed by 케이피엑스 라이프사이언스 주식회사 filed Critical 케이피엑스 라이프사이언스 주식회사
Publication of WO2012018235A2 publication Critical patent/WO2012018235A2/fr
Publication of WO2012018235A3 publication Critical patent/WO2012018235A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to a process for preparing decitabine with improved yield and purity.
  • Decitabine is a drug for myelodysplastic syndromes (MDS), a type of bone marrow cancer. It is a DNA methylation inhibitor that has a therapeutic effect by inhibiting DNA methylation and has a therapeutic response rate three times higher than that of azacytidine, which has been used before, and all myelodysplastic syndrome regardless of the type of myelodysplastic syndrome in the United States. The drug is being used to treat the syndrome.
  • MDS myelodysplastic syndromes
  • DNA methylation is the process by which methyl groups are added to DNA and as a result abnormal methylation, which inactivates genes important for the regulation of cell differentiation and proliferation, is known to cause various types of tumors.
  • azacytidine which acts primarily on RNA
  • decitabine acts directly on DNA, thereby inhibiting DNA methylation, which causes myelodysplastic syndrome.
  • Decitabine has a dual mechanism of action, including hypomethylation and tumor suppressor gene activation, along with direct and indirect cytotoxic effects of cancer cell suicide.
  • Decitabine also prevents patients with bone marrow dysplasia from receiving blood transfusions, saving patients money and time, as well as avoiding complications related to blood transfusions.
  • step 1 forming a triazine ring using isothiobiuret (step 1), as shown in the following scheme;
  • step 2 a method for producing decitabine, which comprises a step (step 2) of synthesizing decitabine by removing an acetyl group as a protecting group using ammonia.
  • Synthetic method as described above has a low synthesis yield of 33%, there is a problem in the storage and handling of the isocyanate compound which is the starting material of the reaction, there is a problem that is difficult to apply to the mass production process because benzene is used as a carcinogenic solvent.
  • step 1 A step of preparing a halogen-substituted sugar as shown in the following scheme (step 1); There is disclosed a step (step 2) of preparing decitabine through a substitution reaction with 5-azacytosine in which a silyl group is introduced (J. Org. Chem, 1970, 35, 491).
  • the synthesis method as described above has a storage problem because dangerous hydrochloric acid gas is required for the synthesis of halogen-substituted sugar (hereinafter referred to as "halosugar") and halosch lacks its own stability.
  • the time required for the deprotection process is about 3-7 days, so the overall yield is very low, about 7%.
  • a high pressure reactor is required in the deprotection process with ammonia (step 2), which is more inappropriate for commercial production.
  • German patent application DE 2012888 discloses 5-azacytosine in which protected nucleosides and silyl groups are introduced in excess of tin catalyst and EDC (1-ethyl-3- (3-dimethylaminopropyl) carbodiimide) Mention is made of a process for preparing decitabine using acetonitrile as a solvent.
  • the synthesis method is very difficult to filter tin compounds, such as insoluble tin salts, so that the tin compound remains in decitabine, which is a final material, has a fatal defect in commercially preparing API.
  • tin compounds such as insoluble tin salts
  • the synthetic yield is as low as 21-41%.
  • the present inventors have completed the present invention by improving the yield of decitabine and the purity of decitabine itself, and finding an improved manufacturing method of decitabine excellent in both purity and yield.
  • TMSOTf trimethylsilyltrifluoromethanesulfonate
  • EDC ethylene dichloride
  • step 3 of obtaining a decitabine of the formula (1) in which the acetyl group is deprotected from the compound of formula (5) obtained in step 2.
  • the conventionally mentioned starting material and its synthesis method can be used to selectively produce intermediates having a specific arrangement, but also the intermediates are free amines in which the amine group is not protected by a protecting group. It can be obtained in the form, and by crystallization it can be obtained decitabine with improved purity to 99.5% or more.
  • TMSOTf trimethylsilyltrifluoromethanesulfonate
  • step 3 of obtaining a decitabine of the formula (1) in which the acetyl group is deprotected from the compound of formula (5) obtained in step 2.
  • step 1 is a step of coupling-reacting 5-azacytosine to which the silyl group of Formula 3 is introduced with 1,3,5-triacetyl-2-deoxyribose of Formula 2.
  • step 1 methylene chloride or EDC may be used as the reaction solvent. It is more preferable to use methylene chloride from the viewpoint of facilitating work up after the reaction and increasing the yield.
  • reaction of Step 1 may use Lewis acid as a catalyst.
  • Lewis acid there is no particular limitation on the Lewis acid that can be used, and for example, TMSOTf or the like is preferably used.
  • step 1 is preferably carried out for 12-24 hours at low temperature reaction conditions of 0-5 °C.
  • the reaction product obtained in step 1 has a problem in that the yield is lowered due to structural instability accompanied by heat generation during high temperature conditions or work-up. On the other hand, there exists a problem that reaction rate falls at low temperature below 0 degreeC.
  • step 2 is a step of recrystallization of the reaction product of step 1.
  • Recrystallization of step 2 is preferably carried out using ethyl acetate as the recrystallization solvent.
  • the reaction product represented by the formula (4) obtained as a result of the step 1 is not only an oily product (Oily product) that is not easy to handle, but also isomers of ⁇ and ⁇ forms around the carbon 1 of the furanose ring. Or a mixture of ⁇ -anomers, hereinafter referred to as " ⁇ -anomers" or " ⁇ -anomers.”
  • ⁇ - and ⁇ -anomers present in the form of a mixture are subjected to the recrystallization according to step 2 of the present invention to obtain the non-oil-like formula (4) in the form of a free amine in which trimethylsilyl group (TMS) has been removed.
  • TMS trimethylsilyl group
  • ⁇ -anomers are obtained with high purity of 90% or more.
  • the pyranose ring compound which is present in the final product (decitabine), which has been presented as a conventional problem, affecting the purity of the product, is removed in the reaction process of step 2, thereby improving the purity of the intermediate and the final product.
  • decitabine which has been presented as a conventional problem, affecting the purity of the product
  • step 2 of the present invention preferably performs recrystallization for 1-3 hours. If the recrystallization time is short, proper crystallization of the product does not proceed, and if the recrystallization time is long, product loss due to solubility may occur.
  • step 3 is a step of deprotecting the acetyl group from the decitabine intermediate of the formula (4).
  • sodium methoxide, ammonia, sodium ethoxide, potassium carbonate, etc. may be used as a base in methanol or ethanol solvent.
  • the bases have low solubility in solvents, especially methanol, so that they are easy to remove after the reaction. It is preferable to use sodium methoxide in methanol solvent from the viewpoint of yield, reaction time shortening, minimization of impurities, etc., wherein the sodium methoxide is more preferably used at 28% concentration:
  • the present invention may further comprise the step (step 4) of purifying the decitabine product obtained by performing step 3.
  • the purification step may be carried out by including a purification step (step 4) consisting of dissolving and refluxing the decitabine of the formula (1) in a methanol solvent, concentrated under reduced pressure and stirred at room temperature to recrystallize.
  • a purification step consisting of dissolving and refluxing the decitabine of the formula (1) in a methanol solvent, concentrated under reduced pressure and stirred at room temperature to recrystallize.
  • the present invention provides a process for preparing 1,3,5-triacetyl-deoxyribose of formula (II) comprising steps A, B and C, as shown in Scheme 2:
  • step A Reacting 2-dioxy-D-ribose of Formula 6 with 20-25 ° C. in a methanol solvent in the presence of hydrochloric acid to obtain 2-dioxyribose methylglycoside of Formula 7 (step A);
  • 2-dioxyribose methylglycoside of Formula 7 obtained in step A was dissolved in 20-25 ° C. ethyl acetate solvent, acetic anhydride and pyridine were added, and warmed to 70-80 ° C. to protect with acetyl group. Obtaining 3,5, -diacetyl-2-deoxyribose methylglucoside of (step B); And
  • step C Dissolving 3,5, -diacetyl-2-dioxyribose methylglucoside of Formula 8 obtained in step B in an acetic acid solvent at 20-25 ° C., followed by addition of acetic anhydride and sulfuric acid to react (step C) :
  • step A is a step of protecting the 2-dioxy-D-ribose of formula 6 with a hydroxy group of carbon number 1 as a methoxy group.
  • Step A may be carried out at a reaction temperature of 20-25 ° C. in a methanol solvent in the presence of hydrochloric acid.
  • the reaction of step A is preferably carried out for 0.5-4 hours. If the reaction time is performed for more than 4 hours, there is a problem in that impurities in the form of pyranose rings, which are structural isomers of the furanose ring, are generated, and if the reaction time is performed in less than 0.5 hours, there is a problem that the yield is lowered.
  • the hydrochloric acid catalyst used in the step A is preferably neutralized after the reaction is completed.
  • step B is a step of protecting the remaining hydroxy group of the reaction product of step A protected with a methoxy group with an acetyl group.
  • Step B may be carried out by reacting acetic anhydride in the presence of a pyridine base.
  • Ethyl acetate may be used as the reaction solvent.
  • the reaction temperature of methylglycoside of formula (7) is dissolved in ethyl acetate, the solution is added acetic anhydride and pyridine and then warmed to 70-80 ° C. to protect hydroxy groups of carbon 3 and 5 of the compound of formula (7) with acetyl. Let's do it.
  • the protection reaction is preferably carried out for 12-24 hours.
  • step C is a step of changing the methoxy group of carbon number 1 introduced as a result of performing step A to an acetyl group.
  • Step C may be carried out by reacting acetic anhydride under a concentrated sulfuric acid catalyst. It is preferable to use acetic acid as a reaction solvent, and it is preferable to carry out by maintaining the reaction temperature at 0-10 °C.
  • step C is preferably performed within 1 hour and then terminate the reaction quickly. If the reaction is carried out for more than 1 hour, there is a problem in that the entire reaction product is transformed into a polymer mixture, which makes the operation impossible. Due to the rapid termination of the reaction, some compounds of formula (7) which are not completely converted into the compounds of formula (2) which are starting materials of the present invention are present.However, the reaction of step 1 of the decitabine preparation method of the present invention As a result, they can contribute to an increase in overall yield.
  • the present invention also provides a process for preparing decitabine of Formula 1 from a compound of Formula 2 comprising steps i) to vi), as shown in Scheme 3:
  • step i) to step iii) can be carried out in the same manner as the above-described step A to step C.
  • steps iv) to vi) may be performed in the same manner as in the above-described steps 1 to 3.
  • Such a preparation method according to the present invention can selectively produce only intermediates having a specific arrangement using a starting material and a synthesis method thereof, which are not mentioned in the prior art, and also the intermediates are not preamines in which the amine group is not protected by a protecting group. It can be obtained in the form of (free amine), and by crystallization it can be obtained decitabine with improved purity to more than 99.5%.
  • Step 2 Preparation of Recrystallization Product (Formula 5)
  • Example 2 Except for using 14.5% by weight ammonia dissolved in methanol instead of 28% sodium methoxide in step 3 of Example 1, the same method as in Example 1 was performed on 20 g of decitabine obtained before purification To give decitabine (6.14 g, yield 42.0%, purity 99.28%).
  • Example 2 The same method as in Example 1 for 20 g of decitabine obtained before purification, except that it was a low temperature reaction using sodium ethoxide and ethanol instead of 28% sodium methoxide and a solvent of methanol in step 3 of Example 1. Was carried out to give decitabine (3.2 g, yield 22%).
  • Example 1 was carried out in the same manner as in Example 1 with respect to 1 g of decitabine obtained before purification except for using potassium carbonate instead of 28% sodium methoxide and crystallization using MTBE in step 3 of Example 1 was obtained (semi-solid, purity 88%).
  • Step A Preparation of 2-Deoxyribose Methylglycoside (Formula 7)
  • Step B Preparation of 3,5-diacetyl-2-deoxyribose methylglycoside (Formula 8)
  • Temp. Initial 100 ° C. for 2 minutes, rise to 10 ° C./min., Final 250 ° C. for 5 minutes

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
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Abstract

La présente invention concerne un procédé de préparation de décitabine assurant un meilleur rendement et une plus grande pureté, et plus précisément un procédé de préparation de décitabine assurant un meilleur rendement et une plus grande pureté comprenant les étapes suivantes : une étape (étape 1) qui consiste à faire réagir du 1,3,5‑triacétyl‑2‑désoxyribose et de la 5‑azacytosine dans laquelle est introduit un groupe silyle dans un chlorure de méthylène ou un solvant EDC en présence d'un acide de Lewis triflate de TMSO ; une étape (étape 2) qui consiste à obtenir un produit intermédiaire par cristallisation du produit de réaction obtenu à l'étape 1 en utilisant de l'acétate d'éthyle comme solvant de cristallisation : et une étape (étape 3) qui consiste à obtenir, à partir du produit intermédiaire cristallisé à l'étape 2, de la décitabine sous la forme d'un produit final dans lequel un groupe acétyle est déprotégé. Selon la présente invention, la formation d'isomères peut être réduite au minimum en utilisant un nouveau matériau de départ et un nouveau procédé pour sa synthétisation, et la pureté du produit final peut être portée à 99,5 % ou au-delà au moyen d'un nouveau précurseur qui est cristallisé sous la forme d'une amine libre au lieu d'une amine protégée. En conséquence, le procédé selon la présente invention peut être utilisé efficacement pour la préparation de décitabine d'une grande pureté et avec un rendement élevé.
PCT/KR2011/005724 2010-08-05 2011-08-04 Procédé de préparation de décitabine assurant un meilleur rendement et une plus grande pureté WO2012018235A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
KR10-2010-0075554 2010-08-05
KR1020100075554A KR101241321B1 (ko) 2010-08-05 2010-08-05 수율 및 순도가 개선된 데시타빈의 제조방법

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WO2012018235A3 WO2012018235A3 (fr) 2012-05-03

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103897008A (zh) * 2012-12-28 2014-07-02 石药集团中奇制药技术（石家庄）有限公司 一种地西他滨及其中间体的制备方法

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
BRPI0408561A (pt) * 2003-03-20 2006-03-21 Microbiol Quimica Farmaceutica métodos para manufatura de 2'-desoxi-59-l-nucleosìeos
US7250416B2 (en) * 2005-03-11 2007-07-31 Supergen, Inc. Azacytosine analogs and derivatives
EP2050757A1 (fr) * 2007-10-10 2009-04-22 Cilag AG Procédé de fabrication de 2' -désoxy-5-azacytidine (Décitabine)
EP2318423B1 (fr) * 2008-08-08 2014-05-07 ScinoPharm Taiwan, Ltd. Procédé de fabrication de nucléosides de 5-azacytosine et leurs dérivés

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103897008A (zh) * 2012-12-28 2014-07-02 石药集团中奇制药技术（石家庄）有限公司 一种地西他滨及其中间体的制备方法

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WO2012018235A3 (fr) 2012-05-03
KR20120013537A (ko) 2012-02-15

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