WO2005058926A1 - New process for preparing diisopropyl ((1-((2-amino-6-chloro-9h-purin-9-yl)methyl)cyclopropyl)oxy)methylphosphonate - Google Patents

New process for preparing diisopropyl ((1-((2-amino-6-chloro-9h-purin-9-yl)methyl)cyclopropyl)oxy)methylphosphonate Download PDF

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WO2005058926A1
WO2005058926A1 PCT/KR2004/003258 KR2004003258W WO2005058926A1 WO 2005058926 A1 WO2005058926 A1 WO 2005058926A1 KR 2004003258 W KR2004003258 W KR 2004003258W WO 2005058926 A1 WO2005058926 A1 WO 2005058926A1
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Prior art keywords
formula
compound
folbwing
reaction
methyl
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PCT/KR2004/003258
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French (fr)
Inventor
Suk-Kyoon Yoon
Cheol-Min Kim
Byung-Ran So
Ki-Kon Lee
Kun-Hye Nam
Man-Young Yoon
Sang-Chul Choi
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Lg Life Sciences Ltd.
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Publication of WO2005058926A1 publication Critical patent/WO2005058926A1/en

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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07FACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/02Phosphorus compounds
    • C07F9/547Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6561Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
    • C07F9/65616Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings containing the ring system having three or more than three double bonds between ring members or between ring members and non-ring members, e.g. purine or analogs
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07FACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/02Phosphorus compounds
    • C07F9/547Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6561Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/66Phosphorus compounds
    • A61K31/675Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12Antivirals

Definitions

  • the compound of formula (7) to be used as starting material in the present invention can be prepared from the compound of formula (3).
  • the compound of formula (3) can be reacted with sodium azide to give the compound of the folbwing formula (10),

Abstract

The present invention relates to a new process for preparing the compound of formula (1) which is important intermediate for preparation of nucleoside analog of the compound of formula (2) effective as antiviral agent, in particular hepatitis B viral agent.

Description

Description NEW PROCESS FOR PREPARING DIISOPROPYL ((l-((2-AMINO-6-CHLORO-9H-PURIN-9-YL)METHYL)CYCLOP ROPYL)OXY)METHYL-PHOSPHONATE
[i]
[2] TECHNICAL FIELD
[3]
[4] The present invention relates to a new process for preparing the compound of the following formula (1)
[5]
Figure imgf000002_0001
[6]
[7] in which 1 2
[8] R and R are same or different and each represents straight-chain or branched C -C -alkyl,
[9]
[ 10] which is important intermediate for preparation of nucleoside analog of the compound of the following formula (2) [11]
Figure imgf000002_0002
[12]
[13] effective as antiviral agent, in particular hepatitis B viral agent.
[14] [15] BACKGROUND ART [16]
[17] The compound of formula (2) is a stock medicine substance which is devebped as new therapeutic agent for hepatitis B (Korean Patent Application No. KR2002-0003051, WO 02/057288), and is the most important intermediate for preparation of the compound of formula (2). Purine derivative such as formula (2) has anticancer and antiviral activity, and 10 or more kinds of compounds including AZT, 3TC, ACV, etc. are on the market. However, since selectivity between two nitrogens of imidazole ring is always present in introducing purine radical, there have been a number of studies to solve this problem (Tetrahedron, 1990, 46, 6903; Helv. Chim. Acta, 1989, 72, 1495; J. Org. Chem, 1995, 60, 2902; EP 0967213). In particular, since the problem caused by regioselectivity can be solved if purine ring is synthesized from pyrimidine ring, there have been a number of studies focused on that ( Tetrahedron, 2000, 56, 5077.; J. Org. Chem., 1975, 40, 3141.: WO 94/07892.: J. Med. Chem., 2001, 44, 170).
[18]
[19] A prior process known in Korean Patent Application No. KR2002-0003051 and WO 02/057288 prepares the objective compound of the above formula (1), N-7 isomer, the compound of the following formula (5),
[20]
Figure imgf000003_0001
[21]
[22] in which 1 2
[23] R and R are same or different and each represents straight-chain or branched C -C -alkyl, 4
[24]
[25] and the compound of the following formula (6)
Figure imgf000004_0001
[27]
[28] in which 1 2
[29] R and R are as defined above,
[30]
[31] which is a reactant of two molecules of purine, in a ratio of 2.5 : 1 : 1 by reacting { l-[(diisopropoxyphosphoryl)methoxy]cycfopropyl}methylmethane sulfonate of the following formula (3)
[32]
Figure imgf000004_0002
[33]
[34] in which 1 2
[35] R and R are as defined above,
[36]
[37] with 2-amino-6-chforopurine of the following formula (4)
[38]
Figure imgf000004_0003
[39]
[40] in the presence of sodium hydride as base.
[41]
[42] The above process can be illustrated by the following Reaction Scheme (1).
[43]
[44] Reaction Scheme 1
[45]
Figure imgf000005_0001
[46]
[47] However, the process has a couple of disadvantages such as low selectivity and formation of by-products. [48]
[49] DISCLOSURE OF THE INVENTION
[50] [51] The present inventors have performed extensive studies to obtain the compound of formula (1) in high yield. As a result, the inventors have found out that regioselectivity and the formation of by-products can be simultaneously solved by reacting the compound of the following formula (7)
[52]
Figure imgf000005_0002
[53]
[54] iini which 1 2
[55] RR! a and R are same or different and each represents straight-chain or branched C -C -alkyl, 4
[56]
[57] prepared from the compound of formula (3) with 2,5-diamino-4,6-dichforopyrimidine of the following the formula (8)
[58]
Figure imgf000005_0003
[60] Therefore, an object of the present invention is to provide an efficient process for preparing the objective compound of formula (1) by using new starting material. [61] [62] The present invention relates to a process for preparing the compound of formula (1), salt, hydrate, or solvate thereof, [63] [64] characterized in that amine compound of formula (7) is reacted with 2,5-diamino-4,6-dichforopyrimidine compound of formula (8) in the presence of base to give the compound of the following formula (9),
[65]
Figure imgf000006_0001
[66]
[67] in which 1 2
[68] R and R are as defined above,
[69]
[70] and then the obtained compound of formula (9) is cyclized with triethyl or- thoformate or diethoxy methylacetate in the presence of catalytic amount of hydrochloric acid.
[71]
[72] The process according to the present invention can be illustrated by the folbwing Reaction Scheme (2).
[73]
[74] Reaction Scheme 2
Figure imgf000007_0001
Figure imgf000007_0002
[76]
[77] Both selectivity and formation of by-productes caused by oveneaction which are disadvantages of the prior process can be solved by using the process according to the present invention.
[78]
[79] The compound of formula (7) to be used as starting material in the present invention can be prepared from the compound of formula (3). Thus, the compound of formula (3) can be reacted with sodium azide to give the compound of the folbwing formula (10),
[80]
Figure imgf000007_0003
[81]
[82] in which [83] R1 and R2 are as defined above, [84] [85] the obtained compound of formula (10) is reacted with triphenylphosphine to give the compound of formula (7). [86] [87] The process for preparation of the compound of formula (7) can be illustrated by the folbwing Reaction Scheme (3). [88] [89] Reaction Scheme 3 [90] sodium azide
Figure imgf000008_0001
D DMMFF ater/dioxane
Figure imgf000008_0002
10
Figure imgf000008_0003
[91]
[92] Below, the present invention is illustrated in more detail.
[93]
[94] BEST MODE FOR CARRYING OUT THE INVENTION
[95]
[96] First, the compound of formula (3) is dissolved in DMF. DMF is used in an amount of 1.5 to 6 M , preferably 2 to 4 mil per g, of the compound of formula (3). To the reaction mixture is added dropwise sodium azide in an amount of 1 to 1.2 equivalents based on the compound of formula (3), and then the mixture is reacted at room temperature for about 20 hours. After completion of the reaction, the reaction mixture is quenched with water and then extracted with ethyl acetate, and the solvent is distilled off under reduced pressure to give the compound of formula (10). This compound is used in the next reaction without any further purification.
[97]
[98] The compound of formula (10) is dissolved in tetrahydrofuran or the mixture of dioxane and water. The organic solvent and water are used in a mixture of 2: 1 to 10: 1, preferably 2: 1 to 4: 1, and the total amount thereof is 2 to 6 M , preferably 2 b 4 m! per g, of the compound of formula (10). 1 to 1.2 equivalents of triphenylphosphine is added to the reaction mixture to carry out reduction reaction. After completion of the reaction, the reaction mixture is quenched with IN of HC1, and by-products are removed by using ethyl acetate. The reaction mixture is basified with IN of NaOH, and then extracted with methylene chbride to give the compound of formula (7).
[99]
[100] The obtained compound of formula (7) and 2,5-diamino-4,6-dichbropyrimidine of formula (8) are dissolved in butanol. Pyrimidine compound is used in an amount of 1 to 1.3 equivalents, preferably 1.15 equivalents, based on the compound of formula (7), and butanol is used in an amount of 5 to 20 M , preferably 5 to 8 M per g, of the compound of formula (7). To the reaction mixture are added dropwise one or more selected from the group consisting of triethylamine, sodium carbonate, potassium carbonate, cesium carbonate, and sodium bicarbonate as base. Among them, sodium carbonate is the most suitable base, and used in the amount of 2 equivalents based on the the compound of formula (7). The reaction mixture is reacted at 90 to 100 °C for 4 to 24 hours. After completion of the reaction, butanol is distilled off under reduced pressure. To the remaining reaction mixture is added saturated aqueous ammonium chbride solution, and the mixture is extracted with methylene chbride. Methylene chbride is distilled off under reduced pressure, and the resultant is used in the next reaction without any further purification.
[101]
[102] To the obtained compound of formula (9) are added dropwise triethyl orthoformate or diethoxy methylacetate, and catalytic amount of cone, hydrochbric acid. Triethyl orthoformate or diethoxy methylacetate is used in an amount of 5 to 10 M per g, of the compound of formula (9), and cone, hydrochbric acid is used at 1% by volume to the triethyl orthoformate or diethoxy methylacetate. The reaction is carried out at room temperature ~ 80 °C . After completion of the reaction, the reaction mixture is extracted with methylene chbride or ethyl acetate, preferably ethyl acetate, and then solvent is distilled off under reduced pressure therefrom. To the resultant is added dropwise t-butyl methyl ether in an amount of 5 to 20 M per g, of the compound of formula (9) to give the compound of formula (1) as solid.
[103]
[104] The compound of formula (1) prepared in the above manner can be subjected to conventional conversion process to give salt, hydrate, or solvate, of the compound of formula (1).
[105]
[106] The folbwing examples are presented to illustrate further the present invention. However, it should be understood that these examples are intended to illustrate the present invention, and cannot limit the technical scope of the present invention .
[107]
[108] Example 1
[109] Preparation of amine compound of formula (7)
[HO]
[111] Mesylate of formula (3) (20 g, 58.1 mmol) was dissolved in DMF (60 mH ) at room temperature. To the solution was added dropwise sodium azide (3.8 g, 58.5 mmol), which was then reacted at room temperature for 19 hours. Water (300 M ) was added dropwise to the mixture to complete the reaction, and the reaction mixture was extracted with ethyl acetate (3 xl50 M ). Extracted organic layer was distilled under reduced pressure to give a crude product (10) (17 g). To the mixture was added water (20 mH ), tetrahydrofuran (40 mH ), and triphenylphosphine (15.2 g, 58.0 mmol), and the resulting mixture was then reacted at 55 °C . After completion of the reaction, IN of HC1 (120 M ) was added dropwise to the reaction mixture, and by-products were extracted out with ethyl acetate (100 M ). To the resultant is added dropwise IN of NaOH (130 M ) to basify, and the resulting mixture was then extracted with methylene chbride (2 xl50 τ ) to give the title compound (11 g, yield of 71%).
[112] ι
[113] H NMR (DMSO d ) δ: 0.51(m, 2H), 0.69(m, 2H), 1.23(m, 12H), 2.67(s, 2H), 6 3.73(d, J=6Hz, 2H), 4.57(m, 4H).
[114]
[115] Example 2
[116] Preparation of diisopropyl ({l-[(2-amino-6-chloro-9 -purin-9-yl)methyl] cyclopropyl}oxy)methylphosphonate (1)
[117]
[118] 2,5-Diamino-4,6-dichbropyrimidine (8) (2.4 g, 13.5 mmol), the compound of formula (7) (3 g, 11.7 mmol), and sodium carbonate (2.48 g, 23.4 mmol) were added dropwise to butanol (24 mβ ), and the solution was reacted at 90 °C . When completion of the reaction was confirmed by HPLC, butanol was distilled off under reduced pressure therefrom. To the resultant was added dropwise saturated aqueous ammonium chbride solution (36 mβ ), which was then extracted twice with methylene chbride (36 mβ ). Methylene chbride was distilled under reduced pressure therefrom, and the resultant was then used in the next reaction without any further purification.
[119] ι
[120] H NMR (CD OD) δ: 0.67(m,2H), 0.72(m, 2H), 1.20(m, 12H), 3.60(d, J=3.9Hz, 3 2H), 3.82(d, J=7.2Hz, 2H), 3.95(bs, 2H), 4.53(m, 2H), 5.64(bs, 2H), 6.59(m, 1H).
[121]
[122] To the obtained compound of formula (9) were added dropwise triethyl orthoformate (41 M ) and cone, hydrochbric acid (0.41 M ), and the solution was reacted at 80 °C . When completion of the reaction was confirmed by HPLC, IN of HC1 (41 M ) was added dropwise thereto. After about 2 hours, ethanol formed during the reaction was distilled off under reduced pressure therefrαn. The resultant was extracted with ethyl acetate (2 x 50 M ), and then ethyl acetate was distilled under reduced pressure therefrαn. To the resultant was added dropwise t-butyl methyl ether (41 M ), and the resultant was crystallized at ran temperature to give the title compound (2.3 g, yield of 75%).
[123] ι
[124] H NMR (CDC1 ) δ: 0.85~0.88(m, 2H), 1.02~1.05(m, 2H), 1.26(d, J=3.0Hz, 6H), 3 1.31(d, J=6.0Hz, 6H), 3.84(d, J=4.0Hz, 2H), 4.23(s, 2H), 4.71(m, 2H), 5.20(s, NH , 2 2H), 8.17(s, 1H). [125] [126] EFFECT OF THE INVENTION
[127]
[128] When pyrimidine ring together with desired purine ring was synthesized from the compound of formula (7), starting material, according to the present process, the selectivity and formation of by-products of formula (6) caused by oveneaction which are disadvantages of the prior process can be improved, and thus the total yield can be increased.

Claims

Claims
[ 1 ] 1. A process for preparing the compound of the folbwing formula ( 1 ), salt, hydrate, or solvate thereof
in which 1 2 R and R are same or different and each represents straight-chain or branched C -C -alkyl, 4
[3] characterized in that amine compound of formula (7)
Figure imgf000012_0002
in which 1 2 R and R are as defined above, [5] is reacted with 2,5-diamino-4,6-dichbropyrimidine compound of the folbwing formula (8)
Figure imgf000012_0003
in the presence of base to give the compound of the folbwing formula (9),
Figure imgf000012_0004
in which 1 2 R and R are as defined above,
[8] and then the obtained compound of formula (9) is cyclized with triethyl orthoformate or diethoxy methylacetate in the presence of catalytic amount of hydrochbric acid.
[9] 2. The process according to claim 1 wherein the compound of formula (7) is obtained by reacting the compound of the folbwing formula (3)
Figure imgf000013_0001
in which 1 2 R and R are as defined in Claim 1, [11] with sodium azide to obtain the compound of the folbwing formula (10)
Figure imgf000013_0002
in which 1 2 R and R are as defined above,
[13] and reacting the obtained compound of formula (10) with triphenylphophine.
[14] 3. The process according to claim 1 wherein the base is sodium carbonate.
[15] 4. The process according to claim 1 wherein 2,5-diamino-4,6-dichbropyrimidine of formula (8) is empbyed from 1 to 1.3 equivalents based on the amine compound of formula (7).
PCT/KR2004/003258 2003-12-19 2004-12-10 New process for preparing diisopropyl ((1-((2-amino-6-chloro-9h-purin-9-yl)methyl)cyclopropyl)oxy)methylphosphonate WO2005058926A1 (en)

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KR1020030093946A KR20050062944A (en) 2003-12-19 2003-12-19 New process for preparing diisopropyl ((1-((2-amino-6-chloro-9h-purin-9-yl)methyl)cyclopropyl)oxy)-methylphosphonate
KR10-2003-0093946 2003-12-19

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8093229B2 (en) 2005-03-30 2012-01-10 Conforma Therapeutics Corporation Alkynyl pyrrolo[2,3-d]pyrimidines and related analogs as HSP90-inhibitors
CN106432330A (en) * 2015-08-11 2017-02-22 天津科伦药物研究有限公司 Intermediate compound of medicine LB80380 and preparing method and application thereof

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5302585A (en) * 1990-04-20 1994-04-12 Institute Of Organic Chemistry And Biochemistry Of The Academy Of Sciences Of The Czech Republic Use of chiral 2-(phosphonomethoxy)propyl guanines as antiviral agents
US5977089A (en) * 1996-07-26 1999-11-02 Gilead Sciences, Inc. Antiviral phosphonomethoxy nucleotide analogs having increased oral bioavailability
EP0967213A1 (en) * 1998-06-23 1999-12-29 SUMIKA FINE CHEMICALS Co., Ltd. Process for preparing tetraalkylammonium salt of 6-halogenopurine derivative
WO2002057288A1 (en) * 2001-01-19 2002-07-25 Lg Life Sciences Ltd. Novel acyclic nucleoside phosphonate derivatives, salts thereof and process for the preparation of the same

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5302585A (en) * 1990-04-20 1994-04-12 Institute Of Organic Chemistry And Biochemistry Of The Academy Of Sciences Of The Czech Republic Use of chiral 2-(phosphonomethoxy)propyl guanines as antiviral agents
US5977089A (en) * 1996-07-26 1999-11-02 Gilead Sciences, Inc. Antiviral phosphonomethoxy nucleotide analogs having increased oral bioavailability
EP0967213A1 (en) * 1998-06-23 1999-12-29 SUMIKA FINE CHEMICALS Co., Ltd. Process for preparing tetraalkylammonium salt of 6-halogenopurine derivative
WO2002057288A1 (en) * 2001-01-19 2002-07-25 Lg Life Sciences Ltd. Novel acyclic nucleoside phosphonate derivatives, salts thereof and process for the preparation of the same

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8093229B2 (en) 2005-03-30 2012-01-10 Conforma Therapeutics Corporation Alkynyl pyrrolo[2,3-d]pyrimidines and related analogs as HSP90-inhibitors
CN106432330A (en) * 2015-08-11 2017-02-22 天津科伦药物研究有限公司 Intermediate compound of medicine LB80380 and preparing method and application thereof

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KR20050062944A (en) 2005-06-28
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AR047055A1 (en) 2006-01-04

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