WO2010068171A1 - A process for the preparation of 3- [ (2r) tetrahydrofuran-2- ylmethyl] -2-thioxo-l, 2, 3, 7-tetrahydro-6h-purin-6-one - Google Patents

A process for the preparation of 3- [ (2r) tetrahydrofuran-2- ylmethyl] -2-thioxo-l, 2, 3, 7-tetrahydro-6h-purin-6-one Download PDF

Info

Publication number
WO2010068171A1
WO2010068171A1 PCT/SE2009/051401 SE2009051401W WO2010068171A1 WO 2010068171 A1 WO2010068171 A1 WO 2010068171A1 SE 2009051401 W SE2009051401 W SE 2009051401W WO 2010068171 A1 WO2010068171 A1 WO 2010068171A1
Authority
WO
WIPO (PCT)
Prior art keywords
process according
compound
formula
temperature
base
Prior art date
Application number
PCT/SE2009/051401
Other languages
French (fr)
Inventor
Vahak Abedi
Bengt Leonard ÅSLUND
Anders BÖGEVIG
Helen Bolin
Jenny Ekegren
Roberto Giuseppe Paolo Gatti
Simone Zaramella
Original Assignee
Astrazeneca Ab
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 Astrazeneca Ab filed Critical Astrazeneca Ab
Publication of WO2010068171A1 publication Critical patent/WO2010068171A1/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
    • C07D473/22—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 one oxygen and one sulfur atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/04—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D307/10—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
    • 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
    • C07D405/06—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 linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • the present invention relates to a new and more efficient process suitable for large scale preparation of 3-[(2i?)tetrahydrofuran-2-ylmethyl]-2-thioxo-l,2,3,7-tetrahydro-6H-purin-6- one.
  • the present invention also relates to new intermediates prepared therein suitable for large scale preparation of said compound.
  • Conditions or disorders that may be specifically mentioned include multiple sclerosis, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and stroke, as well as other inflammatory diseases or conditions such as asthma, chronic obstructive pulmonary disease, cystic fibrosis, idiopathic pulmonary fibrosis, acute respiratory distress syndrome, sinusitis, rhinitis, psoriasis, dermatitis, uveitis, gingivitis, atherosclerosis, inflammatory bowel disease, renal glomerular damage, liver fibrosis, sepsis, proctitis, rheumatoid arthritis, and inflammation associated with reperfusion injury, spinal cord injury and tissue damage/scarring/adhesion/rejection.
  • Lung cancer has also been suggested to be associated with high MPO levels. The compound is also expected to be useful in the treatment of pain.
  • the present invention relates to a process for preparing a compound of formula (I)
  • X is S, and Y is O; R 1 represents hydrogen;
  • R 2 represents ((R)-2-Tetrahydrofuran-2-yl)methyl
  • R 3 and R 4 are hydrogen; or a pharmaceutically acceptable salt thereof;
  • Ci_ 6 alkyl referred to herein denotes a straight or branched chain alkyl group having from 1 to 6 carbon atoms. Examples of such groups include methyl, ethyl, 1 -propyl, n-butyl, iso-butyl, tert-butyl, pentyl and hexyl.
  • Ci_ 4 alkyl is to be interpreted analogously.
  • Ci_6alkoxy denotes a straight or branched chain alkoxy group having from 1 to 6 carbon atoms. Examples of such groups include methoxy, ethoxy, 1-propoxy, 2-propoxy and tert-butoxy.
  • the term "Ci_4alkoxy” is to be interpreted analogously.
  • halogen referred to herein denotes fluoro, chloro, bromo and iodo.
  • An alcohol is, for example, an aliphatic alcohol comprising a Ci_6 branched or straight chain.
  • An alcohol is, for example, methanol, ethanol, n-propanol, n-butanol or tert-butanol (such as ethanol).
  • An alkali metal is, for example, sodium or potassium.
  • An alkoxide is, for example, a deprotonated alcohol.
  • this process defines an efficient and high yielding process for the transformation of a compound of formula (II) to a compound of formula (I). Furthermore, this process provided the compound of formula (I) in short time, with high purity and also will provide the desired polymorph from the reaction mixture without the need for recrystallization. It will be appreciated that when R 3 in formula (I) represents hydrogen, the compound of formula (I) may be in tautomeric form. All such tautomers and mixtures of tautomers are included within the scope of the present invention.
  • One embodiment of the present invention relates to a process, wherein the isolating process is a crystallisation process.
  • the crystallization is performed in an aqueous solution of solvents selected from DMSO, an alcohol, l,3-dimethyl-2- imidazolidinone and sulfolane.
  • the crystallization process is performed below 60 0 C.
  • the crystallization process is performed in a temperature range of from 15 to 50 0 C.
  • said crystallisation process is performed by adjusting the pH through the addition of base and then the addition of acid .
  • Suitable bases include organic and inorganic bases.
  • Suitable acids include inorganic, such as hydrochloric, sulfuric, phosphoric and nitric acids or suitable organic acids.
  • said acid is hydrochloric acid.
  • said base is selected from NaOH, LiOH, KOH, NH 3 , NaOMe, NaOEt, KOMe, KOEt, LiOEt and NH 4 OH.
  • One embodiment of the present invention relates to a process, wherein the step a is performed at a temperature of from 60 to 90 0 C. According to another embodiment of the present invention, said temperature is about 70
  • One embodiment of the present invention relates to a process, wherein said process is performed in a polar protic or aprotic solvent selected from DMSO, an alcohol, 1,3- dimethyl-2-imidazolidinone and sulfolane.
  • a polar protic or aprotic solvent selected from DMSO, an alcohol, 1,3- dimethyl-2-imidazolidinone and sulfolane.
  • said solvent is ethanol, methanol or DMSO.
  • One embodiment of the present invention relates to a process, wherein said process also comprises a filtration step.
  • the present invention also relates to a process for preparing a compound of formula (II) by a) reacting a compound of formula (V)
  • 1-2 equivalents of ethyl 2- cyano(hydroxyimino)acetate is used in said process.
  • the above-described process is an efficient and high yielding process for conversion of a compound of formula (II) to a compound of formula (I) without the need for isolation of the formed intermediate. Further, it will allow the transformation of a compound of formula (V), in presence of compound of formula (VI), to a compound of formula (II) in high yield and high capacity. Also, said process will allow an efficient and high yielding conversion of the compound of formula (VII) to a compound of formula (II) and/or said process will provide an efficient and high yielding conversion of the compound of formula (VII) to the compound of formula (II) using catalytic hydrogenation. Furthermore, said process will provide the isolation of the compound of formula (II) in high yield and purity.
  • One embodiment of the present invention relates to a process, wherein the base used for step a) is selected from metal alkoxides such as sodium alkoxides or lithium alkoxides such as sodium propyloxide, sodium t-butoxide, lithium methoxide, lithium ethoxide, lithium propyloxide, lithium isopropyloxide, lithium t-butoxide.
  • said base is sodium methoxide or sodium ethoxide.
  • step a) is performed at a temperature of from about 45-70 0 C. According to another embodiment of the present invention, said temperature is about 55 0 C.
  • One embodiment of the present invention relates to a process, wherein the solvent used in step a) is selected from Ci_6 aliphatic alcohols .
  • said solvent is methanol or ethanol.
  • step bl is performed at a temperature of from 35 to 45 0 C.
  • said temperature is about 40 0 C
  • One embodiment of the present invention relates to a process, wherein the solvent used in step bl) is ammonium hydroxide.
  • One embodiment of the present invention relates to a process, wherein the catalyst used in step b2) is platinum on carbon (1 to 10% w/w platinum).
  • the catalyst used in step b2) is platinum on carbon (1 to 10% w/w platinum).
  • Other suitable catalysts include rhodium catalysts and platinum catalysts that are doped with other metals, such as vanadium, palladium, iron or AI 2 O 3 .
  • One embodiment of the present invention relates to a process, wherein the solvent used in step b2) or bl) is selected from aqueous ammonium hydroxide, ammonia dissolved in alcohols, alcohols, water or a mixture thereof. According to another embodiment of the present invention, said solvent is a mixture of ammonium hydroxide, ammonia in methanol and ethanol.
  • One embodiment of the present invention relates to a process, wherein step b2) is performed at a temperature of from 20 to 50 0 C. According to another embodiment of the present invention, said temperature is about 30 0 C.
  • step b2 relates to a process, wherein step b2) is performed at a pressure of from 1 to 15 bar. According to another embodiment of the present invention, said pressure is from 2 to 4 bar.
  • the present invention also relates to a process for obtaining a compound of formula (V) by reacting a compound of formula (VIII) X O
  • R 2 , R 5 and X are as defined in claim 1 and R 5 is aryl, Ci_ 6 alkyl or benzyl, wherein said aryl Ci_ 6 alkyl or benzyl is unsubstituted or optionally substituted with one or more substituents selected from Ci_ 6 alkyl, Ci_ 6 alkoxy, nitro and halogen.
  • One embodiment of the present invention relates to a process, wherein said base is selected from alkali metal hydroxides, alkali metal Ci_ 6 alkoxides, and ammonium hydroxide.
  • said base is sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, potassium ethoxide, lithium methoxide, lithium ethoxide or potassium methoxide.
  • One embodiment of the present invention relates to a process, wherein the amount of base is in the range of 0.01 mole equivalent to 1-2 mole equivalent. According to one embodiment of the present invention, the amount of base is from 0.01 to 0.1 equivalent.
  • One embodiment of the present invention relates to a process, wherein the solvent used is selected from water, Ci_6 alcohols, aromatic hydrocarbons, ethers, DMSO, sulfolane, DMF, N-methyl-2- pyrrolidone (NMP), and mixtures thereof.
  • the solvent used is selected from water, Ci_6 alcohols, aromatic hydrocarbons, ethers, DMSO, sulfolane, DMF, N-methyl-2- pyrrolidone (NMP), and mixtures thereof.
  • One embodiment of the present invention relates to a process, wherein the reaction is performed in a temperature of from 20 0 C-110 0 C. According to one embodiment of the present invention, said temperature is from 60 to 90 0 C.
  • One embodiment of the present invention relates to the use of the process(es) disclosed above, for obtaining a compound of formula (I).
  • the present invention also relates to a hydrolysis process for conversion of a compound of formula (VIII) or a compound of formula (IX) to obtain a compound of formula (II) using catalytic amount of base.
  • the above process is an efficient process for hydrolysis of a compound of formula (VIII) or formula (IX) which will provide the isolation of a compound of formula (V) in high yield. Furthermore, said process is an efficient and short process for hydrolysis of intermediate compound of formula (IX) or (VIII) to a compound of formula (V), which uses catalytic amount of base thereby avoiding the formation of large volumes of salts and the need for their filtration and which gives very high yield >95% and purity.
  • Figure 1 is an X-ray powder diffractogram of 3-[(2i?)tetrahydrofuran-2-ylmethyl]-2- thioxo- 1 ,2,3 ,7-tetrahydro-6H-purin-6-one.
  • Butyl acetate (22 mL) was added to the combined filtrates and the obtained solution was distilled to remove -60% of the total volume. Butyl acetate (64 mL) was charged again and the distillation was continued in order to remove -40% of the total volume in the reactor. The temperature of the mixture was adjusted to -55 0 C and isooctane (110 mL) was added, while the temperature was maintained at -55 0 C. After said addition was completed, the temperature was reduced to 5 0 C for 5 hours and maintained at that temperature for additional 5 hours.
  • vessel A The content of vessel A (after the completed reaction) was charged to the contents of vessel B, while the temperature was maintained at 40 ⁇ 5 0 C. Vessel A was rinsed with ammonium hydroxide (25% aqueous, 0.50 L) and charged to vessel B. After the reaction was completed (30 minutes from completion of the addition, 98% conversion by HPLC), the mixture was heated to 50 0 C and was then filtered while hot. The filter-cake was washed with a hot (50 0 C) ethanolic (1.50 L) solution of ammonium hydroxide (25% aqueous, 0.50 L). The mother liquor and the wash liquid were combined and distilled (50- 80 0 C) under vacuum to reduce the pH and the volume.
  • the distillation was continued until the pH reached below 8.8 (water was added when needed to maintain agitation). Once the desired pH was obtained, the volume of the mixture was adjusted (>20 L/kg of starting material), the mixture was cooled to 7 0 C in a period of 11 hours, and the temperature was maintained at 7 0 C for 12 hours. The mixture was then filtered and the cake washed with a solution of ethanol and water (ethanol 0.30 L, water 2.70 L), ethanol (3.00 L), and ethanol (4.80 L).
  • the agitated mixture was heated (55 0 C) and the solution of ethyl 2- cyano(hydroxyimino)acetate (14.O g, 107 mmole) in ethanol (21 mL) was added during a period of 2 to 3 hours. After the reaction was completed ( ⁇ 2 hours, >97% conversion by HPLC), the temperature was lowered to 20 0 C.
  • the slurry from vessel A was transferred into a hydrogenating reactor that contains the catalyst (5.12 g, 5.5 w/w% platinum on carbon, 1.4 mmole). The slurry container was rinsed with a solution of ammonia in methanol (7 M, 48 mL).
  • the hydrogenation vessel was sealed, temperature adjusted to 30 0 C, and purged with nitrogen through three consecutive cycles of vacuum and nitrogen charges. The vessel was then evacuated and pressurized to 4 bar with hydrogen. After the reaction was complete ( ⁇ 4 hours) the reaction mixture was filtered through celite and rinsed with an ammonium hydroxide solution (25% aqueous, 24 mL). The filtrate was then transferred into an agitated reactor and heated to 50 0 C, at which point the addition of HCl (6 M) was initiated ( ⁇ 36 mL water was added, as needed, to maintain a mixable slurry). When the pH has reached 7.5-8 the addition was stopped (35 ml of 6M HCl) and the mixture was cooled to 10 0 C during a period of 10 hours.
  • reaction mixture was cooled to 35 0 C and aqueous NaOH (4.4 M, 411 mmole, 93 mL) was added to adjust the pH ( ⁇ IO).
  • Ethanol 300 mL was added to the filtered solution and then the pH was lowered (5-6) by addition of an aqueous solution of HCl (3.8 M, 616 mmole, 160 mL), whereby the crystallization was initiated.
  • the slurry was then cooled to 10 0 C during a period of 3 hours, and the temperature was maintained at 1O 0 C for least 5 h.
  • the crystals were dissolved in aqueous sodium hydroxide (0.88 L,2.5 M, 2.22 moles, pH>10) and further diluted with water (0.94 L, 3.4 I/Kg) and ethanol (2.26 L, 8.2 I/Kg). After adjusting the temperature to 35 0 C, the pH was adjusted by addition of an aqueous HCl solution (1.59 L, 1.4 M, 2.2 moles, 2 eq), whereby the crystallization was initiated. The slurry was then cooled to 1O 0 C during a period of 3 hours, and was maintained at 10 0 C for at least 5 h.
  • X-ray powder diffraction analysis was performed on samples prepared according to standard methods, for example those described in Giacovazzo, C. et al (1995), Fundamentals of Crystallography, Oxford University Press; Jenkins, R. and Snyder, R. L. (1996), Introduction to X-Ray Powder Diffractometry, John Wiley & Sons, New York; Bunn, C. W. (1948), Chemical Crystallography, Clarendon Press, London; or Klug, H. P. & Alexander, L. E. (1974), X-ray Diffraction Procedures, John Wiley and Sons, New York.
  • X-ray diffraction analyses were performed using a PANalytical X'Pert Pro MPD, equipped with a X'celerator detector, for 1 hour and 36 minutes from 1 to 60° 2 ⁇ with CuKa radiation.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

The present invention relates to a new and more efficient process suitable for large scale preparation of 3-[(2R)tetrahydrofuran-2-ylmethyl]-2-thioxo-1,2,3,7-tetrahydro-6H-purin-6-one.

Description

A process for the preparation of 3- [ (2R) tetrahydrofuran-2- ylmethyl] -2-thioxo-l, 2, 3, 7-tetrahydro-6H-purin-6-one
The present invention relates to a new and more efficient process suitable for large scale preparation of 3-[(2i?)tetrahydrofuran-2-ylmethyl]-2-thioxo-l,2,3,7-tetrahydro-6H-purin-6- one. The present invention also relates to new intermediates prepared therein suitable for large scale preparation of said compound.
BACKGROUND OF THE INVENTION
Processes for preparing thioxantine compounds are described in WO 03/089430, WO
2005/037835 and WO2008/152420.
There is a need for a more convenient and more economically efficient process for the manufacture of 3-[(2i?)tetrahydrofuran-2-ylmethyl]-2-thioxo-l ,2,3,7-tetrahydro-6H-purin- 6-one, especially with regard to large-scale production where factors like cost, manufacturing time, robustness and safety are vital for commercial application. The present invention provides such a process. 3-[(2i?)Tetrahydrofuran-2-ylmethyl]-2-thioxo- l,2,3,7-tetrahydro-6H-purin-6-one is disclosed as an MPO inhibitor meaning that the compound can be used to treat neuroinflammatory diseases. Conditions or disorders that may be specifically mentioned include multiple sclerosis, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and stroke, as well as other inflammatory diseases or conditions such as asthma, chronic obstructive pulmonary disease, cystic fibrosis, idiopathic pulmonary fibrosis, acute respiratory distress syndrome, sinusitis, rhinitis, psoriasis, dermatitis, uveitis, gingivitis, atherosclerosis, inflammatory bowel disease, renal glomerular damage, liver fibrosis, sepsis, proctitis, rheumatoid arthritis, and inflammation associated with reperfusion injury, spinal cord injury and tissue damage/scarring/adhesion/rejection. Lung cancer has also been suggested to be associated with high MPO levels. The compound is also expected to be useful in the treatment of pain.
OUTLINE OF THE PRESENT INVENTION The present invention relates to a process for preparing a compound of formula (I)
Figure imgf000003_0001
(I) wherein:
X is S, and Y is O; R1 represents hydrogen;
R2 represents ((R)-2-Tetrahydrofuran-2-yl)methyl;
R3 and R4 are hydrogen; or a pharmaceutically acceptable salt thereof;
by reacting a) a compound of formula (II)
Figure imgf000003_0002
(Ha) (Nb) (lie) wherein X, Y, R1 and R2 are as defined above;
Figure imgf000003_0003
with a compound of formula (III) (11O
Figure imgf000003_0004
in the presence of a compound of formula (IV) (|V) in a polar solvent at a temperature of from 50 to 100 0C; b) isolating the compound obtained from a). Thus, the desired polymorph is obtained by said process. According to the present invention ((R)-2-tetrahydrofuran-2-yl)methyl is
Figure imgf000004_0001
°
The term "Ci_6alkyl" referred to herein denotes a straight or branched chain alkyl group having from 1 to 6 carbon atoms. Examples of such groups include methyl, ethyl, 1 -propyl, n-butyl, iso-butyl, tert-butyl, pentyl and hexyl. The term "Ci_4alkyl" is to be interpreted analogously.
Unless otherwise indicated, the term "Ci_6alkoxy" referred to herein denotes a straight or branched chain alkoxy group having from 1 to 6 carbon atoms. Examples of such groups include methoxy, ethoxy, 1-propoxy, 2-propoxy and tert-butoxy. The term "Ci_4alkoxy" is to be interpreted analogously.
Unless otherwise indicated, the term "halogen" referred to herein denotes fluoro, chloro, bromo and iodo.
An alcohol is, for example, an aliphatic alcohol comprising a Ci_6 branched or straight chain. An alcohol is, for example, methanol, ethanol, n-propanol, n-butanol or tert-butanol (such as ethanol).
An alkali metal is, for example, sodium or potassium.
An alkoxide is, for example, a deprotonated alcohol.
Hence, this process defines an efficient and high yielding process for the transformation of a compound of formula (II) to a compound of formula (I). Furthermore, this process provided the compound of formula (I) in short time, with high purity and also will provide the desired polymorph from the reaction mixture without the need for recrystallization. It will be appreciated that when R3 in formula (I) represents hydrogen, the compound of formula (I) may be in tautomeric form. All such tautomers and mixtures of tautomers are included within the scope of the present invention.
One embodiment of the present invention relates to a process, wherein the isolating process is a crystallisation process.
According to one embodiment of the present invention, the crystallization is performed in an aqueous solution of solvents selected from DMSO, an alcohol, l,3-dimethyl-2- imidazolidinone and sulfolane.
According to another embodiment of the present invention, the crystallization process is performed below 60 0C.
According to another embodiment of the present invention, the crystallization process is performed in a temperature range of from 15 to 50 0C.
According to another embodiment of the present invention, said crystallisation process is performed by adjusting the pH through the addition of base and then the addition of acid . Suitable bases include organic and inorganic bases. Suitable acids include inorganic, such as hydrochloric, sulfuric, phosphoric and nitric acids or suitable organic acids.
According to yet another embodiment of the present invention, said acid is hydrochloric acid.
According to yet another embodiment of the present invention, said base is selected from NaOH, LiOH, KOH, NH3, NaOMe, NaOEt, KOMe, KOEt, LiOEt and NH4OH.
One embodiment of the present invention relates to a process, wherein the step a is performed at a temperature of from 60 to 90 0C. According to another embodiment of the present invention, said temperature is about 70
0C.
One embodiment of the present invention relates to a process, wherein said process is performed in a polar protic or aprotic solvent selected from DMSO, an alcohol, 1,3- dimethyl-2-imidazolidinone and sulfolane.
According to another embodiment of the present invention, said solvent is ethanol, methanol or DMSO.
One embodiment of the present invention relates to a process, wherein said process also comprises a filtration step.
The present invention also relates to a process for preparing a compound of formula (II) by a) reacting a compound of formula (V)
Figure imgf000006_0001
(V) with a compound of formula (VI)
Figure imgf000006_0002
(Vl) in the presence of a base and at a temperature of from 40 to 70 0C; in the presence of a solvent; whereby a compound of formula (VII) is obtained
Figure imgf000007_0001
or a tautomer thereof; and either: bl) reacting a compound of formula (VII) with sodium dithionite in an aqueous solution; or b2) reacting a compound of formula (VII) with a transition metal catalyst in presence of hydrogen and in the presence of a solvent; wherein R2 and X are as defined above.
According to one embodiment of the present invention, 1-2 equivalents of ethyl 2- cyano(hydroxyimino)acetate is used in said process.
According to one embodiment of the present invention, 2 to 5 equivalent of metal alkoxide is used in said process.
The above-described process is an efficient and high yielding process for conversion of a compound of formula (II) to a compound of formula (I) without the need for isolation of the formed intermediate. Further, it will allow the transformation of a compound of formula (V), in presence of compound of formula (VI), to a compound of formula (II) in high yield and high capacity. Also, said process will allow an efficient and high yielding conversion of the compound of formula (VII) to a compound of formula (II) and/or said process will provide an efficient and high yielding conversion of the compound of formula (VII) to the compound of formula (II) using catalytic hydrogenation. Furthermore, said process will provide the isolation of the compound of formula (II) in high yield and purity.
One embodiment of the present invention relates to a process, wherein the base used for step a) is selected from metal alkoxides such as sodium alkoxides or lithium alkoxides such as sodium propyloxide, sodium t-butoxide, lithium methoxide, lithium ethoxide, lithium propyloxide, lithium isopropyloxide, lithium t-butoxide. According to another embodiment of the present invention, said base is sodium methoxide or sodium ethoxide.
One embodiment of the present invention relates to a process, wherein step a) is performed at a temperature of from about 45-70 0C. According to another embodiment of the present invention, said temperature is about 55 0C.
One embodiment of the present invention relates to a process, wherein the solvent used in step a) is selected from Ci_6 aliphatic alcohols .According to another embodiment of the present invention, said solvent is methanol or ethanol.
One embodiment of the present invention relates to a process, wherein step bl) is performed at a temperature of from 35 to 45 0C. According to another embodiment of the present invention, said temperature is about 40 0C
One embodiment of the present invention relates to a process, wherein the solvent used in step bl) is ammonium hydroxide.
One embodiment of the present invention relates to a process, wherein the catalyst used in step b2) is platinum on carbon (1 to 10% w/w platinum). Other suitable catalysts include rhodium catalysts and platinum catalysts that are doped with other metals, such as vanadium, palladium, iron or AI2O3.
One embodiment of the present invention relates to a process, wherein the solvent used in step b2) or bl) is selected from aqueous ammonium hydroxide, ammonia dissolved in alcohols, alcohols, water or a mixture thereof. According to another embodiment of the present invention, said solvent is a mixture of ammonium hydroxide, ammonia in methanol and ethanol. One embodiment of the present invention relates to a process, wherein step b2) is performed at a temperature of from 20 to 50 0C. According to another embodiment of the present invention, said temperature is about 30 0C.
One embodiment of the present invention relates to a process, wherein step b2) is performed at a pressure of from 1 to 15 bar. According to another embodiment of the present invention, said pressure is from 2 to 4 bar.
The present invention also relates to a process for obtaining a compound of formula (V) by reacting a compound of formula (VIII) X O
HN -^N^ R5 ^2 H
(VIII)
or a compound of formula (IX)
Figure imgf000009_0001
in the presence of a solvent with a base; wherein R2, R5 and X are as defined in claim 1 and R5 is aryl, Ci_6alkyl or benzyl, wherein said aryl Ci_6alkyl or benzyl is unsubstituted or optionally substituted with one or more substituents selected from Ci_6 alkyl, Ci_6 alkoxy, nitro and halogen.
One embodiment of the present invention relates to a process, wherein said base is selected from alkali metal hydroxides, alkali metal Ci_6 alkoxides, and ammonium hydroxide.
According to one embodiment of the present invention, said base is sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, potassium ethoxide, lithium methoxide, lithium ethoxide or potassium methoxide. One embodiment of the present invention relates to a process, wherein the amount of base is in the range of 0.01 mole equivalent to 1-2 mole equivalent. According to one embodiment of the present invention, the amount of base is from 0.01 to 0.1 equivalent.
One embodiment of the present invention relates to a process, wherein the solvent used is selected from water, Ci_6 alcohols, aromatic hydrocarbons, ethers, DMSO, sulfolane, DMF, N-methyl-2- pyrrolidone (NMP), and mixtures thereof.
One embodiment of the present invention relates to a process, wherein the reaction is performed in a temperature of from 20 0C-110 0C. According to one embodiment of the present invention, said temperature is from 60 to 90 0C.
One embodiment of the present invention relates to the use of the process(es) disclosed above, for obtaining a compound of formula (I).
The present invention also relates to a hydrolysis process for conversion of a compound of formula (VIII) or a compound of formula (IX) to obtain a compound of formula (II) using catalytic amount of base.
The above process is an efficient process for hydrolysis of a compound of formula (VIII) or formula (IX) which will provide the isolation of a compound of formula (V) in high yield. Furthermore, said process is an efficient and short process for hydrolysis of intermediate compound of formula (IX) or (VIII) to a compound of formula (V), which uses catalytic amount of base thereby avoiding the formation of large volumes of salts and the need for their filtration and which gives very high yield >95% and purity.
Figure 1 is an X-ray powder diffractogram of 3-[(2i?)tetrahydrofuran-2-ylmethyl]-2- thioxo- 1 ,2,3 ,7-tetrahydro-6H-purin-6-one.
EXAMPLES
The present invention is illustrated with the following non- limiting examples. General method:
The processes of the present invention can be summarized by the following process scheme
Figure imgf000011_0001
reducing agent solvent
isolate
Figure imgf000011_0002
Scheme 1 wherein X, Y, R2, R3 and R4 are as defined for formula (I) above; and wherein R5 is aryl, Ci_6 alkyl or benzyl, wherein said aryl, Ci_6alkyl or benzyl is unsubstituted or optionally substituted with one or more substituents selected from Ci_6 alkyl, Ci_6 alkoxy, nitro and halogen.
Scheme 2 below summarizes a process according to the present invention of preparing 3- [(2i?)tetrahydrofuran-2-ylmethyl]-2-thioxo-l,2,3,7-tetrahydro-6H-purin-6-one.
Figure imgf000012_0001
Scheme 2
Example 1 l-[(2R)-Tetrahydrofuran-2-ylmethyl] thiourea
Figure imgf000012_0002
Λ/-({[(2i?)-Tetrahydrofuran-2-ylmethyl]amino}carbonothioyl)benzamide (22.1 g, 83.8 mmole) was added to a solution of potassium hydroxide (5.87 g, 88.9 mmole) in ethanol (70 mL) and heated to 80 0C. After the reaction was completed, (2 hours, >98% conversion by HPLC) the obtained mixture was cooled down (10 0C) and during the cooling, ethyl acetate (7.0 mL, 71.5 mmole, 0.85 eq) was charged. The precipitate was filtered off and the cake was washed with ethyl acetate (35 mL). Butyl acetate (22 mL) was added to the combined filtrates and the obtained solution was distilled to remove -60% of the total volume. Butyl acetate (64 mL) was charged again and the distillation was continued in order to remove -40% of the total volume in the reactor. The temperature of the mixture was adjusted to -55 0C and isooctane (110 mL) was added, while the temperature was maintained at -55 0C. After said addition was completed, the temperature was reduced to 5 0C for 5 hours and maintained at that temperature for additional 5 hours. The slurry was filtered and the filter cake was washed with pre-mixed n-butyl acetate (11 mL) and isooctane (34 mL). The filter cake was dried under vacuum at 4O0C for a minimum of 12 hours to yield 13.4 g of l-[(2i?)-tetrahydrofuran-2-ylmethyl]thiourea (86% yield, 98% HPLC purity, 91% 1H NMR assay)
Example 2 l-[(2/?)-Tetrahydrofuran-2-ylmethyl] thiourea
Figure imgf000013_0001
Potassium methoxide (25% in MeOH, 0.11 ml, 0.378 mmole) was added to a stirring solution of N-( { [(2i?)-tetrahydrofuran-2-ylmethyl] amino } carbonothioyl)benzamide ( 10. Og, 37.8 mmole) in methanol (20 mL) and heated to reflux. After the reaction was completed (30 minutes, full conversion by TLC), the mixture was cooled to 55 0C. Butyl acetate (20 mL) was then added and the obtained solution was distilled to remove -40% of the total volume. Butyl acetate (10 mL) was added again and the distillation was continued until -40% of the total volume in the reactor was removed. The temperature of the mixture was adjusted to -50 0C and cyclohexane (50 ml) was added while the temperature was maintained at -50 0C. After the completion of the addition of cyclohexane, the temperature was reduced during 2 hours to 5 0C and then maintained for an additional hour. The slurry was filtered and the filter cake was washed with pre-mixed n-butyl acetate (5 ml) and cyclohexane (15 ml). The filter cake was dried under vacuum at 40 0C to yield 5.68 g of 1- [(2R)-tetrahydrofuran-2-ylmethyl]thiourea (94% yield, >99% HPLC purity, 100% 1H NMR assay)
Example 3
5,6-Diamino-l-[(2R)tetrahydrofuran-2-ylmethyl]-2-thioxo-2,3-dihydropyrimidin-
4(lH)-one
ΗNJγNΗ2
° In vessel A (preparation of 6-amino-5-nitroso- 1 -[(2i?)-tetrahydrofuran-2- ylmethyl]-2-thioxo-2,3-dihydropyrimidin-4(lH)-one): l-[(2i?)-tetrahydrofuran-2- ylmethyl]thiourea (1.00 kg, 5.93 mole, 1.0 eq) was added to a solution of sodium methoxide in methanol (30% w/w, 3.85 L, 20.8 mole, 3.5 eq). The agitated mixture was heated (55 0C) and a solution of ethyl 2-cyano(hydroxyimino)acetate (1.30 kg, 8.89 mole, 1.5 eq) in ethanol (1.75 L) was added during a period of 2 to 3 hours. After the reaction was completed (~2 hours, >97% conversion by HPLC), the temperature was lowered to 25 0C. In vessel B: aqueous ammonium hydroxide (25% , 8.6 L) was added to a slurry of sodium dithionite (2.75 kg, 11.9 mole, 2.0 eq) in water (3.00 L), and the resulting slurry was heated to 40 0C. The content of vessel A (after the completed reaction) was charged to the contents of vessel B, while the temperature was maintained at 40±5 0C. Vessel A was rinsed with ammonium hydroxide (25% aqueous, 0.50 L) and charged to vessel B. After the reaction was completed (30 minutes from completion of the addition, 98% conversion by HPLC), the mixture was heated to 50 0C and was then filtered while hot. The filter-cake was washed with a hot (50 0C) ethanolic (1.50 L) solution of ammonium hydroxide (25% aqueous, 0.50 L). The mother liquor and the wash liquid were combined and distilled (50- 80 0C) under vacuum to reduce the pH and the volume. The distillation was continued until the pH reached below 8.8 (water was added when needed to maintain agitation). Once the desired pH was obtained, the volume of the mixture was adjusted (>20 L/kg of starting material), the mixture was cooled to 7 0C in a period of 11 hours, and the temperature was maintained at 7 0C for 12 hours. The mixture was then filtered and the cake washed with a solution of ethanol and water (ethanol 0.30 L, water 2.70 L), ethanol (3.00 L), and ethanol (4.80 L). The filter cake was dried under vacuum at 55 0C for a minimum of 24 hours to yield 0.207 kg of 5,6-diamino-l-[(2i?)tetrahydrofuran-2-ylmethyl]-2-thioxo-2,3- dihydropyrimidin-4(lH)-one (>70% yield, >99% purity and w/w assay). 1H NMR (DMSO-d6): δ 11-12.5 (br s, IH), 5.98 (s, 2 H), 4.72 (br d, IH), 4.33 (br s, IH), 4.21-4.27 (m, IH), 3.83-3.88 (m, IH), 3.63-3.69 (m, IH), 3.50 (br s, 2H), 1.77-2. 02 (m, 3H), 1.65-1.57 (m, IH).
Example 4
S^-Diamino-l-IClRJtetrahydrofuran-l-ylmethyll-l-thioxo-l^-dihydropyrimidin-
4(lH)-one
Figure imgf000015_0001
In vessel A (preparation of 6-amino-5-nitroso-l-[(2i?)-tetrahydrofuran-2-ylmethyl]-2- thioxo-2,3-dihydropyrimidin-4(lH)-one): l-[(2i?)-tetrahydrofuran-2-ylmethyl]thiourea (12 g, 71.7 mmole) was added to a solution of sodium methoxide in methanol (30% w/w, 49.7 mL, 265 mmole). The agitated mixture was heated (55 0C) and the solution of ethyl 2- cyano(hydroxyimino)acetate (14.O g, 107 mmole) in ethanol (21 mL) was added during a period of 2 to 3 hours. After the reaction was completed (~2 hours, >97% conversion by HPLC), the temperature was lowered to 20 0C. The slurry from vessel A was transferred into a hydrogenating reactor that contains the catalyst (5.12 g, 5.5 w/w% platinum on carbon, 1.4 mmole). The slurry container was rinsed with a solution of ammonia in methanol (7 M, 48 mL). The hydrogenation vessel was sealed, temperature adjusted to 30 0C, and purged with nitrogen through three consecutive cycles of vacuum and nitrogen charges. The vessel was then evacuated and pressurized to 4 bar with hydrogen. After the reaction was complete (~4 hours) the reaction mixture was filtered through celite and rinsed with an ammonium hydroxide solution (25% aqueous, 24 mL). The filtrate was then transferred into an agitated reactor and heated to 500C, at which point the addition of HCl (6 M) was initiated (~36 mL water was added, as needed, to maintain a mixable slurry). When the pH has reached 7.5-8 the addition was stopped (35 ml of 6M HCl) and the mixture was cooled to 10 0C during a period of 10 hours. The mixture was then filtered and the cake washed with a solution of ethanol and water (ethanol 3.6 mL, water 36 mL), ethanol (32.4 mL), and ethanol (57.6 mL). The filter cake was dried under vacuum at 55 0C for a minimum of 24 hours to yield 9.85 g of 5,6-diamino-l-[(2i?)tetrahydrofuran-2- ylmethyl]-2-thioxo-2,3-dihydropyrimidin-4(lH)-one (>57% yield, 99% purity and w/w assay). 1H NMR (DMSO-de): δ 8.5-12.00 (br s, IH), 6.01 (s, 2 H), 4.71-4.74 (br d, IH), 4.35 (br s, IH), 4.21-4.27 (m, IH), 3.83-3.88 (m, IH), 3.63-3.68 (m, IH), 3.53 (br s, 2H), 1.76-2.02 (m, 3H), 1.57-1.66 (m, IH).
Example 5 S-IClRJTetrahydrofuran-l-ylmethyll-l-thioxo-l^^^-tetrahydro-όH-purin-ό-one
Figure imgf000016_0001
A DMSO (105 mL) solution of 5,6-diamino-l-[(2i?)tetrahydrofuran-2-ylmethyl]-2-thioxo- 2,3-dihydropyrimidin-4(lH)-one (50.0 g, 205 mmoles, 1 eq) was added to a mixture of formamidine acetate (30.3 g, 288 mmole, 1.40 eq) in DMSO (95 mL) at 65 0C (20 mL DMSO used for rinsing). After the reaction was completed (3 hours, >97% conversion by HPLC), the reaction mixture was cooled to 35 0C and aqueous NaOH (4.4 M, 411 mmole, 93 mL) was added to adjust the pH (≥IO). Ethanol (300 mL) was added to the filtered solution and then the pH was lowered (5-6) by addition of an aqueous solution of HCl (3.8 M, 616 mmole, 160 mL), whereby the crystallization was initiated. The slurry was then cooled to 10 0C during a period of 3 hours, and the temperature was maintained at 1O0C for least 5 h. The mixture was then filtered and the cake washed with a solution of ethanol and water (ethanol 70 mL, water 130 mL), water (200 mL), and ethanol (200 mL). The filter cake was dried under vacuum at 40 0C for a minimum of 24 hours to yield 49.8 g of 3- [(2i?)tetrahydrofuran-2-ylmethyl]-2-thioxo-l,2,3,7-tetrahydro-6H-purin-6-one (95% yield, >99% HPLC purity, 99% w/w assay).
Example 6 S-IClRJTetrahydrofuran-l-ylmethyll-l-thioxo-l^^^-tetrahydro-όH-purin-ό-one
Figure imgf000016_0002
Ethanol (2.75 L, 10.0 L/Kg), formamidine acetate (165.4 g, 1.6 moles, 1.4 eq.), and 5,6- diamino-l-[(2i?)tetrahydrofuran-2-ylmethyl]-2-thioxo-2,3-dihydropyrimidin-4(lH)-one (275 g, 1.11 mole, 1.0 eq) were charged to the reactor, the agitation was started and the mixture was heated to 75 0C. After the reaction was completed (3 hours, HPLC >97% conversion), the reaction mixture was cooled (25 0C) and the product was filtered off. The crystals were dissolved in aqueous sodium hydroxide (0.88 L,2.5 M, 2.22 moles, pH>10) and further diluted with water (0.94 L, 3.4 I/Kg) and ethanol (2.26 L, 8.2 I/Kg). After adjusting the temperature to 35 0C, the pH was adjusted by addition of an aqueous HCl solution (1.59 L, 1.4 M, 2.2 moles, 2 eq), whereby the crystallization was initiated. The slurry was then cooled to 1O0C during a period of 3 hours, and was maintained at 10 0C for at least 5 h. The mixture was then filtered and the cake washed with ethanol (0.70 L), water (0.74 L), water (1.13 L), and ethanol (1.13 L). The filter cake was dried under vacuum at 40 0C for a minimum of 24 hours to yield 278 g of 3-[(2i?)tetrahydrofuran-2-ylmethyl]-2- thioxo-l,2,3,7-tetrahydro-6/f-purin-6-one (97% yield, >99% HPLC purity, 98% w/w assay). Identity by 1H NMR (500 MHz, DMSO-d6); δ (ppm) 13.82 (br s, IH), 12.45 (s, IH), 8.15 (s, IH), 4.58 (m, IH), 4.38-4.5538 (m, 2H), 3.56-3.862 (m, 2H), 1.80-1.94 (m, 2H), 1.74-1.88 (m, 2H).
Results
Identity of 3-[(2i?)tetrahydrofuran-2-ylmethyl]-2-thioxo-l ,2,3,7-tetrahydro-6H-purin-6-one by X-Ray Powder Diffraction using CuKα-radiation (1.5406 A) is shown in figure 1. The 3-[(2i?)tetrahydrofuran-2-ylmethyl]-2-thioxo-l,2,3,7-tetrahydro-6H-purin-6-one produced is Form A.
X-ray powder diffraction analysis (XRPD) was performed on samples prepared according to standard methods, for example those described in Giacovazzo, C. et al (1995), Fundamentals of Crystallography, Oxford University Press; Jenkins, R. and Snyder, R. L. (1996), Introduction to X-Ray Powder Diffractometry, John Wiley & Sons, New York; Bunn, C. W. (1948), Chemical Crystallography, Clarendon Press, London; or Klug, H. P. & Alexander, L. E. (1974), X-ray Diffraction Procedures, John Wiley and Sons, New York. X-ray diffraction analyses were performed using a PANalytical X'Pert Pro MPD, equipped with a X'celerator detector, for 1 hour and 36 minutes from 1 to 60° 2Θ with CuKa radiation.

Claims

1. A process for preparing a compound of formula (I)
Figure imgf000019_0001
(I) wherein:
X is S, and Y is O;
R1 represents hydrogen;
R2 represents (R)-2-tetrahydrofuran-2-ylmethyl;
R3 and R4 are hydrogen; or a pharmaceutically acceptable salt thereof; comprising the steps of reacting a) a compound of formula (II)
Figure imgf000019_0002
(Ha) (lib) (lie) wherein X, Y, R1 and R2 are as defined above;
Figure imgf000019_0003
with a compound of formula (III) (11O
Figure imgf000019_0004
in the presence of a compound of formula (IV) (|V) in a polar solvent at a temperature of from 50 to 100 0C; b) isolating the compound obtained from a).
2. A process according to claim 1, wherein the isolating process is a crystallisation process.
3. A process according to claim 2, wherein the crystallization process is performed below 60 0C.
4. A process according to claim 2, wherein the crysallization process is performed in a temperature range of from 15 to 50 0C.
5. A process according to any one of claims 2 to 4, wherein said crystallisation process is performed by adjusting the pH through the addition of base and then the addition of acid.
6. A process according to claim 5, wherein said acid is hydrochloric acid.
7. A process according to claim 5, wherein said base is selected from NaOH, LiOH, KOH, NH3, NaOMe, NaOEt, KOMe, KOEt, LiOEt and NH4OH.
8. A process according to any one of claims 1 to 7, wherein the step a is performed at a temperature of from 60 to 90 0C.
9. A process according to claim 8, wherein said temperature is about 70 0C.
10. A process according to any one of claims 1 to 9, wherein said process is performed in a solvent selected from DMSO, an alcohol, l,3-dimethyl-2-imidazolidinone and sulfolane.
11. A process according to claim 10, wherein said solvent is ethanol, methanol or DMSO.
12. A process according to any one of claims 1 to 11, wherein said process also comprises a filtration step.
13. A process for preparing a compound of formula (II) comprising the steps of a) reacting a compound of formula (V)
Figure imgf000021_0001
(V) with a compound of formula (VI)
Figure imgf000021_0002
(Vl) in the presence of a base and at a temperature of from 40 to 70 0C; in the presence of a solvent; whereby a compound of formula (VII) is obtained
Figure imgf000021_0003
(Vila) (VIIb) (VIIc) or a tautomer thereof; and either: bl) reacting a compound of formula (VII) with sodium dithionite in an aqueous solution; or b2) reacting a compound of formula (VII) with a transition metal catalyst in presence of hydrogen and in the presence of a solvent; wherein R2 and X are as defined in claim 1.
14. A process according to claim 13, wherein the base used for step a) is selected from metal alkoxides.
15. A process according to claim 14, wherein said base is sodium methoxide or sodium ethoxide.
16. A process according to any one of claims 13 to 15, wherein step a) is performed at a temperature of from about 45 to 70 0C.
17. A process according to any one of claims 13 to 16, wherein the solvent used in step a) is selected from Ci_6 aliphatic alcohols.
18. A process according to claim 17, wherein said solvent is methanol or ethanol.
19. A processs accoring to any one of claims 13 to 18, wherein step bl) is performed at a temperature of from 35 to 45 0C.
20. A process according to any one of claims 13 to 19, wherein the solvent used in step bl) is aqueous ammonium hydroxide.
21. A process according to any one of claims 13 to 18, wherein the catalyst used in step b2) is platinum on carbon (1 to 10% w/w platinum).
22. A process according to any one of claims 13 to 21, wherein the solvent used in step b2) or bl) is selected from aqueous ammonium hydroxide, ammonia dissolved in alcohols, alcohols, water or a mixture thereof.
23. A process according to claim 22, wherein said solvent is a mixture of ammonium hydroxide, ammonia in methanol and ethanol.
24. A process according to any one of claims 13 to 18 and claims 21 to 23, wherein step b2) is performed at a temperature of from 20 to 40 0C.
25. A process according to claim 24, wherein said temperature is about 300C.
26. A process according to any one of claims 13 to 18 and claims 21 to 25, wherein step b2) is performed at a pressure of from 1 to 15 bar.
27. A process according to claim 26, wherein said pressure is from 2 to 4 bar.
28. A process for obtaining a compound of formula (V) by reacting a compound of formula (VIII)
X O
HN X N X R5 ϊ H (VIII) or a compound of formula (IX)
Figure imgf000023_0001
in the presence of a solvent with a base; wherein R2 and X are as defined in claim 1 and R5 is aryl, Ci_6 alkyl or benzyl, wherein said aryl, Ci_6 alkyl or benzyl is unsubstituted or optionally substituted with one or more substituents selected from Ci_6 alkyl, Ci_6 alkoxy, nitro and halogen.
29. A process according to claim 28, wherein said base is selected from alkali metal hydroxides, alkali metal Ci_6 alkoxides, and ammonium hydroxide.
30. A process according to claim 29, wherein said base is sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, potassium ethoxide, lithium methoxide, lithium ethoxide or potassium methoxide.
31. A process according to any one of claims 28 to 30, wherein the amount of base is in the range of 0.01 mole equivalent to 2 mole equivalent.
32. A process according to claim 31, wherein the amount of base is from 0.01 to 0.1 equivalent.
33. A process according to any one of claims 28 to 32, wherein the solvent used is selected from water, Ci_6 alcohols, aromatic hydrocarbons, ethers , DMSO, sulfolane, DMF, NMP, and mixture thereof.
34. A process according to any one of claims 28 to 33, wherein the reaction is performed in a temperature of from 20 to 110 0C.
35. A process according to claim 34, wherein said temperature is from 60 to 90 0C.
36. Use of a process according to any one of claims 13 to 35 for obtaining a compound of formula (I).
37. A hydrolysis process for conversion of a compound of (VIII) or a compound of formula (IX) to obtain a compound of formula (II) using catalytic amount of base.
PCT/SE2009/051401 2008-12-12 2009-12-11 A process for the preparation of 3- [ (2r) tetrahydrofuran-2- ylmethyl] -2-thioxo-l, 2, 3, 7-tetrahydro-6h-purin-6-one WO2010068171A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US12205408P 2008-12-12 2008-12-12
US61/122,054 2008-12-12

Publications (1)

Publication Number Publication Date
WO2010068171A1 true WO2010068171A1 (en) 2010-06-17

Family

ID=42242954

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/SE2009/051401 WO2010068171A1 (en) 2008-12-12 2009-12-11 A process for the preparation of 3- [ (2r) tetrahydrofuran-2- ylmethyl] -2-thioxo-l, 2, 3, 7-tetrahydro-6h-purin-6-one

Country Status (1)

Country Link
WO (1) WO2010068171A1 (en)

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003089430A1 (en) * 2002-04-19 2003-10-30 Astrazeneca Ab Thioxanthine derivatives as myeloperoxidase inhibitors
WO2005037835A1 (en) * 2003-10-17 2005-04-28 Astrazeneca Ab Novel thioxanthine derivatives for use as inhibitors of mpo
WO2007120097A1 (en) * 2006-04-13 2007-10-25 Astrazeneca Ab Thioxanthine derivatives and their use as inhibitors of mpo
WO2007120098A1 (en) * 2006-04-13 2007-10-25 Astrazeneca Ab Thioxanthine derivatives and their use as inhibitors of mpo
WO2008152420A1 (en) * 2007-06-13 2008-12-18 Astrazeneca Ab New compounds 892
WO2009025617A1 (en) * 2007-08-23 2009-02-26 Astrazeneca Ab Combinations containing mpo inhibitors against neuroinflammatory disorders

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003089430A1 (en) * 2002-04-19 2003-10-30 Astrazeneca Ab Thioxanthine derivatives as myeloperoxidase inhibitors
WO2005037835A1 (en) * 2003-10-17 2005-04-28 Astrazeneca Ab Novel thioxanthine derivatives for use as inhibitors of mpo
WO2007120097A1 (en) * 2006-04-13 2007-10-25 Astrazeneca Ab Thioxanthine derivatives and their use as inhibitors of mpo
WO2007120098A1 (en) * 2006-04-13 2007-10-25 Astrazeneca Ab Thioxanthine derivatives and their use as inhibitors of mpo
WO2008152420A1 (en) * 2007-06-13 2008-12-18 Astrazeneca Ab New compounds 892
WO2009025617A1 (en) * 2007-08-23 2009-02-26 Astrazeneca Ab Combinations containing mpo inhibitors against neuroinflammatory disorders

Similar Documents

Publication Publication Date Title
KR101096499B1 (en) Method for the production of telmisartan
TWI539951B (en) Process for the preparation of 4-{4-[({[4-chloro-3-(trifluoromethyl)-phenyl]amino}carbonyl)amino]-3-fluorophenoxy}-n-methylpyridine-2-carboxamide, its salts and monohydrate
CN101528700B (en) Process for the preparation of imatinib and intermediates thereof
WO2014020555A2 (en) An improved process for the preparation of dabigatran etexilate mesylate
JP7189932B2 (en) Intermediates useful for the synthesis of selective inhibitors of protein kinases and processes for their preparation
US7868207B2 (en) Process for producing 1-(3,4-dichlorobenzyl)-5-octylbiguanide or a salt thereof
US10017472B2 (en) Hydrate of 2-isopropoxy-5-methyl-4-(piperidin-4-yl) aniline dihydrochloride, preparation method and use of the same
US7220863B2 (en) Process for preparing 2-aminopyridine derivatives
JP3930736B2 (en) Method for producing pyridinemethanol compound
US6248891B1 (en) Synthesis of acridine derivative multidrug-resistant inhibitors
WO2010068171A1 (en) A process for the preparation of 3- [ (2r) tetrahydrofuran-2- ylmethyl] -2-thioxo-l, 2, 3, 7-tetrahydro-6h-purin-6-one
CN115667222B (en) Method for preparing GLP-1 receptor agonist
CN107652271A (en) A kind of Topiroxostat crystal formation I preparation method
KR101012134B1 (en) Process for preparing imatinib or mesylate thereof
JP4433365B2 (en) Process for producing 4- (2-methyl-1-imidazolyl) -2,2-diphenylbutanamide
CN110128413B (en) 5-acetyl-4- (N-substituted carbazolyl) -6-methyl-3, 4-dihydropyrimidine-2-ketone and preparation method thereof
JP2015038053A (en) Method for producing 4-(2-methyl-1-imidazolyl)-2,2-phenylbutane amide
US20100063292A1 (en) Process for the preparation of trifluoroethoxytoluenes.
TWI844663B (en) Process for the production of substituted 2-[2-(phenyl)ethylamino]alkaneamide derivatives
CN114315710B (en) Method for preparing or purifying regorafenib
JP5087059B2 (en) Process for producing 4- (2-methyl-1-imidazolyl) -2,2-diphenylbutanamide
CN110577520B (en) Preparation method of 6-nitro-4-substituted amino quinazoline derivative
CN113784944A (en) Process for producing substituted 2- [2- (phenyl) ethylamino ] alkanamide derivatives
CN117285469A (en) Preparation method of Entecavir intermediate
CN117229216A (en) Preparation method of entecavir intermediate

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 09832206

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 09832206

Country of ref document: EP

Kind code of ref document: A1