Title of Invention | METHOD FOR MANUFACTURING OF 4,5,6,7-TETRAHYDROISOXAZOLO[5,4-C9]PYRIDIN-3-OL(THIP) |
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Abstract | The present invention relates to a new method of preparing gaboxadol (THIP), which is useful for treating sleep disorders. In particular a method of preparing THIP comprising reacting a compound of formula (8b) or a salt thereof with an acid, typically a mineral acid, to obtain THIP as an acid addition salt. The present invention also relates to several intermediates. |
Full Text | The term "heteroaryl" as used herein refers to 5- to 6- membered aromatic systems containing 1 to 5 carbon atoms and one or more heteroatoms selected from O, S or N, such as 5-membered monocyclic rings such as oxathiazoles, dioxazoles, dithiazoles, oxadiazoles, thiadiazoles, triazoles, isoxazoles, oxazoles, isothiazoles, thiazoles, imidazoles, pyrazoles, pyrroles, furan(s) or thiophene(s), e.g. 3//-l,2,3-oxathiazole, 1,3,2-oxathiazole, 1,3,2-dioxazole, 3//-l,2,3-dithiazole, 1,3,2-dithiazole, 1,2,3-oxadiazole, 1,2,3-thiadiazole, \H-1,2,3-triazole, isoxazole, oxazole, isothiazole, thiazole, l//-imidazole, l//-pyrazole, \H~ pyrrole, furan or thiophene, or 6-membered monocyclic rings such as oxathiazines, dioxazines, dithiazines, oxadiazines, thiadiazines, triazines, oxazines, thiazines, pyrazines, pyridazines, pyrimidines, oxathiins, dioxins, dithiins, pyridines, pyrans or thiins, e.g. 1,2,3-oxathiazine, 1,2,4-oxathiazine, 1,2,5-oxathiazine, 1,4,2-oxathiazine, 1,4,3-oxathiazine, 1,2,3-dioxazine, 1,2,4-dioxazine, 4//-l,3,2-dioxazine, 1,4,2-dioxazine, 2//-l,5,2-dioxazine, 1,2,3-dithiazine, 1,2,4-dithiazine, 4//-l,3>2-dithiazine, 1,4,2-dithiazine, 2//-l,552-dithiazine, 2H-1,2,3-oxadiazine, 2//-l,2,4-oxadiazine, 2//-l,2,5-oxadiazine, 2//-l,2,6-oxadiazine, 2//-l,3,4-oxadiazine, 2//-l,2,3-thiadiazine, 2//-l,2,4-thiadiazine, 2//-l,2,5-thiadiazine, 2HA,2fi-thiadiazine, 2H-1,3,4-thiadiazine, 1,2,3-triazine, 1,2,4-triazine, 2H-1,2-oxazine, 2H-1,3-oxazine, 2H-1,4-oxazine, 2//-1,2-thiazine, 2H-1,3-thiazine, 2H-1,4-thiazine, pyrazine, pyridazine, pyrimidine, 4//-l,3-oxathiin, 1,4-oxathiin, 4//-l,3-dioxin, 1,4-dioxin, 4//-l,3-dithiin, 1,4-dithiin, pyridine, 2//-pyran or 2//-thiin. The term "acidification" as used herein means that an acid is added to the reaction mixture adjusting the pH to below pH 6.5. The term "a leaving group*1 as used herein is a well-known expression to the skilled chemist, examples being halogens, such as Br, Cl, I, or mesylate or tosylate. The term "a salt" as used herein is intended to mean any salt which a particular compound may form, and is usually intended to comprise acid addition salts, however, the compounds may also form other salts with bases, such as metal salts, eg. sodium salts, and ammonium salts, eg. salts of amines, such as triethylamine. The term "an acid addition salt" as used herein is intended to mean any acid addition salt which a particular compound may form upon reaction of the compound with the acid in a solvent, as known to the skilled person in the art. Suitable examples are hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like. Other suitable examples are organic salts such as acetic, propionic, glycolic, oxalic, malonic, succinic, citric acid and the like. The term "a mild reducing agent" as used herein is a well-known expression to the skilled chemist, reference is made to Brown, H. C; Krishnamurthy; Tetrahedron, 35, 1979, pp 567-607. Suitable examples are borohydrides. The term "a nucleophile" as used herein is a well-known expression to the skilled chemist, reference is made to "Advanced Organic Chemistry" (3rd edition), Jerry March, Wiley-Interscience. The term "a soft nucleophile" as used herein is also described in "Advanced Organic Chemistry" (3rd edition), Jerry March, Wiley-Interscience. Suitable examples are Cl", Br-,r,orNC-SThe term "a dehydrating agent" as used herein is a well-known expression to the skilled chemist, and is intended to cover agents, such as thionylchloride, a chloroformate such as isobutyl chloroformate, or a carbodiimide such as DCI/DCC. Description of the invention The present invention relates to a new method of manufacturing the compound 4,5,6,7-tetrahydroisoxazolo[5,4-c9]pyridin-3-ol(THlP). In one aspect the present invention relates to a method of preparing THIP comprising the steps: wherein R2 and R3 are independently selected from H, Ci.^alkyl, C2-i2alkenyl, C3.8cycloalkyl, C3.8cycloalkenyl, acyl, aryl, or heteroaryl, optionally substituted with a CM2alkyl, Ci. 12alkoxy, or aryl; and L is a leaving group, to obtain a quarternary salt of formula (4) WE CLAIM: 1. A method of preparing THIP comprising the steps: a) reacting a compound of formula (2) with an alkylating agent of formula (3) wherein R2 and R3 are independently selected from H, C1-12 alkyl, C2-12alkenyl, C3-5cycloalkyl, C3.gcycloalkenyl, acyl, aryl, or heteroaryl, optionally substituted with a C1-12alkyl, C1-. 12alkoxy, or aryl, and L is a leaving group, to obtain a quarternary salt of formula (4) wherein L, R2 and R3 are as defined above, b) reacting the quarternary salt of (4) with a mild reducing agent to obtain a compound of formula (5) wherein R2 and R3 are as defined above, c) reacting a compound of formula (5) with a reagent of formula (6a) wherein R' is C3-12 alkyl, C2-12alkenyl, C3.8cycloalkyl, C3-.8cycloalkenyl, acyl, or aryl optionally substituted with one or more C1-12 alkyl, C1-12 alkoxy, or aryl, X is a leaving group, Y is O or S, ZisO, S orC1-.6alkyl, optionally followed by reaction with a nucleophile, to obtain a mixture of a compound of formula (7a) and a compound of (7b) wherein Y, Z, and R' are as defined above, d) reacting the mixture of (7a) and (7b) with a nucleophile, followed by acidification, to obtain a compound of formula (8a) wherein Y, Z, and R' are as defined above, e) reacting a compound of formula (8a) with an acid to obtain THIP as an acid addition salt. 2. The method of claim 1 wherein step a) is carried out in a polar solvent, such as NMP. 3. The method of any one of claims 1-2, step a), wherein in the alkylating agent of formula (3) R2 and R3 are independently selected from H, methyl, ethyl, ally], phenacyl, phenyl, methoxyphenyl and L is selected from Br, Cl, I, OMs, or OTs. 4. The method of claim 3, wherein the alkylating agent of formula (3) is selected from Mel, EtI, BzBr, p-CH3OC6C6H4CH2zBr, allylBr, and the corresponding mesylates (OMs) and tosylates (OTs). 5. The method of any one of claims 1-4 wherein the reduction in step b) is carried out in alcohol and water, such as aqueous ethanol. 6. The method of any one of claims 1-5 wherein the mild reducing agent in step b) is LiBH4 or NaBH4. 7. The method of any one of claims 1-6, step c), wherein in the reagent of formula (6a) R' is C1-12alkyl, C].]2alkenyl, C3.8cycloalkyl, C3.8cycloalkenyl, acyl, or aryl optionally substituted with a C1-12alkyl, C1-12alkoxy, or aryl, X is selected from Cl, Br, I, Y is O, or S Z is O, or S. 8. The method of claim 7, step c), wherein the reagent of formula (6a) is selected from C1_ 12alkyl chloroformate, such as methyl chloroformate, ethyl chloroformate, or ethyl chlorothiolformate. 9. The method of claim 1, step c), wherein a compound of formula (5) is first protected as a carbonate or carbamate, such as a /-butyl- or 2,2,2-trichloroethylcarbonate/carbarnate, and then reacted with the reagent of formula (6a). 10. The method of any one of claims 1-9, step d), wherein the nucleophile is a soft nucleophile, such as aqueous ammonia, an amine or diamine (such as methylamine, ethylenediamine), thiols, thiolates, sulfides, in an aqueous or organic solution. 11. The method of any one of claims 1-10, step d), wherein the reaction with a nucleophile is followed by acidification by adjusting pH to ≤5. 12. The method of any one of claims 1-11, wherein step d) after reaction with the nucleophile in an aqueous solution is followed by separating the aqueous phase, followed by acidification with an aqueous acid, and extraction into an organic phase. 13. The method of any one of claims 1-12, wherein a compound of formula (8a) or a salt thereof is purified by a process of extraction from one phase to another. 14. The method of any one of claims 1-13, wherein a compound of formula (8a) is obtained in high purity, more than 98%, preferably greater than 99% according to HPLC. 15. The method of any one of claims 1-14, wherein step e) is carried out using a mineral acid. 16. A method of preparing a compound of formula (2) comprising reacting the compound of formula (10) with a dehydrating agent, to obtain compound of formula (2). 17. A compound of formula (2) or a salt thereof. 18. A method of preparing THIP comprising reacting a compound of formula (8a) or a salt thereof wherein R' is C1.12alkyl, C2.]2alkenyl, C3.8cycloalkyl, C3.Bcycloalkenyl, acyl, or aryl optionally substituted with one or more C1-12 alkyl, C1-12 alkoxy, or aryl, Y is O or S, and Z is O, S or C1-.6alkylene, with an acid, typically a mineral acid, to obtain THIP as an acid addition salt. 19. A compound of formula (8a) wherein R' is C1-12 alkyI> C1-12 alkenyI, C3.8cycloalkyl, C3-8cycloalkenyl, acyl, or aryl optionally substituted with one or more C1-12 alkyi, C1-12 alkoxy, or aryl, Y is O or S, Z is O, S or C1.6alkyl, or a salt thereof. 20. A method of preparing THIP comprising the steps: a) reacting a compound of formula (2) with an alkylating agent of formula (3) wherein R2 and R3 are independently selected from H, C1-,.12alkyl, C2_12alkenyl, C3.gcycloalkyl, C3.Rcycloalkenyl, acyl, aryl, or heteroaryl, optionally substituted with a C1-12 alkyl, C1- 12alkoxy, or aryl, and L is a leaving group, to obtain a quarternary salt of formula (4) wherein L, R2 and R3 are as defined above, b) reacting the quarternary salt of (4) with a mild reducing agent to obtain a compound of formula (5) wherein R2 and R3 are as defined above, c2) reacting a compound of formula (5) with a reagent of formula (6b) wherein R is C1-12 alkyl, C2-12alkenyl, C3-8cycloalkyl, C3.8cycloalkenyl, acyl, or aryl optionally substituted with one or more C1.12alkyl, C1-12 alkoxy, or aryl, U is N or CR1, wherein Rl is H, or R, W is O, S or NR\ wherein R4 is H, or R, optionally followed by reaction with a nucleophile, to obtain a mixture of a compound of formula (7c) and a compound of (7d) wherein R is C1-12 alkyl, C2.12alkenyl, C3.8cycloalkyl, C3-8 .acycloalkenyl, acyl, or aryl optionally substituted with one or more C1,.12alkyl, C1-12 alkoxy, or aryl, U' is N or CR1, wherein R1 is H, or R, W is O, S or NR4, wherein R4 is H, or R, (12) reacting the mixture of (7c) and (7d) with a nucleophile, followed by acidification, to obtain a compound of formula (8b) wherein W, U' and R are as defined above, e2) reacting a compound of formula (8b) with an acid to obtain THIP as an acid addition salt. 21. The method of claim 20 wherein step a) is carried out in a polar solvent, such as NMP. 22. The method of any one of claims 20-21, step a), wherein in the alkylating agent of formula (3) R2 and R3 are independently selected from H, methyl, ethyl, allyl, phenacyl, phenyl, methoxyphenyl and L is selected from Br, Cl, I, OMs, or OTs. 23. The method of claim 22, wherein the alkylating agent of formula (3) is selected from Mel, EtI, BzBr,p--CH3OC6H4CH2Br> allylBr, and the corresponding mesylates (OMs) and tosylates (OTs). 24. The method of any one of claims 20-23 wherein the reduction in step b) is carried out in alcohol and water, such as aqueous ethanol, 25. The method of any one of claims 20-24 wherein the mild reducing agent in step b) is LiBH4orNaBH4. 26. The method of any one of claims 20-25, step c2)4 wherein in the reagent of formula (6b) R is C|.6alkyl, C2.6alkenyl, C3.8cycloalkyl, C3_8cycloalkenyl, acyl, or phenyl optionally substituted with a C1-.6alkyl, C1.6alkoxy, or phenyl, U is N or CR1, wherein R1 is H, C1-6 alkyl, C2-6alkenyl, C3.8cycloalkyl, C3.8cycloalkenyl, acyl, or phenyl optionally substituted with a C1-.6alkyl, C^alkoxy, or phenyl, W is O, S or NR4, wherein R4 is H, C1-6 aHcyl, C2.6alkenyl, C3.8cycloalkyl, C3.8cycloalkenyl, acyl, or phenyl optionally substituted with a C1-.6alkyl, C1-.6alkoxy, or phenyl. 27. The method of any one of claims 20-26, step c2), wherein the nucleophile is selected from Cl\ Br\ I, or NC-S". 28. The method of any one of claims 26-27, step c2), wherein the reagent of formula (6b) is selected from an isocyanate such as isopropyl isocyanate or phenyl isocyanate, or an isothiocyanate such as phenyl isothiocyanate, or a ketene. 29. The method of claim 20, step c2), wherein a compound of formula (5) is first protected as a carbonate or carbamate, such as a /-butyl- or 2,2,2-trichloroethylcarbonate/carbamate, and then reacted with the reagent of formula (6b). 30. The method of any one of claims 20-29, step d2), wherein the nucleophile, is a soft nucleophile, such as aqueous ammonia, an amine or diamine (such as methylamine, ethylenediamine), thiols, thiolates, sulfides, in an aqueous or organic solution. 31. The method of any one of claims 20-30, step d2), wherein the reaction with a nucleophile is followed by acidification by adjusting pH to ≤5. 32. The method of any one of claims 20-31, wherein step d2) after reaction with the nucleophile in an aqueous solution is followed by separating the aqueous phase, followed by acidification with an aqueous acid, and extraction into an organic phase. 33. The method of any one of claims 20-32, wherein a compound of formula (8b) or a salt thereof is purified by the process of extraction from one phase to another. 34. The method of any one of claims 20-33, wherein a compound of formula (8b) is obtained in high purity, more than 98%, preferably greater than 99% according to HPLC. 35. The method of any one of claims 20-34, wherein step e2) is carried out using a mineral acid. 36. A method of preparing THIP comprising reacting a compound of formula (8b) or a salt thereof wherein, R isC1-12 alkyl, C2.12alkenyl, C3.8cycloalkyl, C3.8cycloalkenyl, acyl, or aryl optionally substituted with one or more C1-12alkyl, C1-12 alkoxy) or aryl, U' is NH or CHR\ wherein R1 is H, or R, W is 0, S or NR4, wherein R4 is H, or R, with an acid, typically a mineral acid, to obtain THIP as an acid addition salt. 37. A compound of formula (8b) wherein, R is C1-12alkyl, C2.12alkenyl, C3.8cycloalkyl, C3.8cycloalkenyl, acyl, or aryl optionally substituted with one or more C1.12alkyl, C1-12 alkoxy, or aryl, U' is NH or CHR1, wherein R1 is H, or R, W is O, S or NR4, wherein R4 is H, or R, or a salt thereof. Analytical Method HPLC HPLC analyses are performed according to the procedures described below. Standard Preparation To a small sample (0.1 shaken until dissolution was complete. Analytical Procedure The sample was injected, and the area of the desired peak was measured, as was the total area. The product assay was calculated with the formula: Assay% = Sample Area/Total Area. In example A below is described a method of preparing the intermediate isoxazolo[5,4-c]pyridin-3-oI (HIP) 3,N-Dihydroxy-isonicotinamide To a stirred suspension of methyl 3-hydroxy-isonicotinate (176 g; 1.15 mol) in water/ice (50/50, 1700 mL), was added hydroxylamine hydrochloride (127.9 g; 1.84 mol). The temperature fell to -5 °C and then aqueous NaOH solution (454 mL, 28% w/v) was added dropwise keeping the temperature below 5 °C during the addition. Hereafter the reaction mixture was stirred at ambient temperature for 1.5 h followed by heating to 60 °C. At this temperature the pH was adjusted to 5.4 by the addition of aqueous hydrochloric acid (10 M) at which point a heavy precipitate forms. The reaction mixture was then stirred at ambient temperature followed by cooling to 5 °C. The pH was then adjusted to 4.0 by the addition of aqueous hydrochloric acid (10 M), and then was stirred whilst cold for 1,5 h. The crystals were filtered off, rinsed with water (3 x 100 mL), dried on the filter and then dried further at reduced pressure and 40 °C overnight to give 3^-dihydroxy-isonicotinamide (169.3 g, 96%; HPLC purity 98%) as a white solid. NMR data: 'H-NMR (DMSO-d6, 250 MHz) 5 = 7.55 (1H, d, J=6 Hz); 8.11 (1H, d, J=6 Hz); 8.32 (lH,s); 9.56 (1H, s, broad peak); 11.50 (1H, s, broad peak) ppm. Isoxazolof5,4-c]pyridin-3-ol (HIP) Method A To a stirred suspension of 3,Af-dihydroxy-isonicotinamide (50 g; 0.32 mol) in DMF (300 mL), cooled on a water bath at ambient temperature, was added carbonyldiimidazole (DCI) (66.4 g; 0.41 mol. The reaction was stirred over night at ambient temperature. The next day the solvent was removed under reduced pressure at 70 °C and the residue was dissolved in water and cooled on ice. The pH of the solution (= 7.5) was adjusted to 4.5 by the addition of an aqueous solution of hydrochloric acid (ca 65 mL, 10 M). The desired product crystallised heavily from the solution. The slurry was evaporated to ca. 2/3 volume to remove traces of DMF, cooled on ice for a couple of hours and filtered. The crystals so obtained were rinsed twice with water and twice with ethanol and dried under reduced pressure at 60 °C overnight to give isoxazolo[5,4-c]pyridin-3-ol (41.7 g, 96 %; HPLC purity >99 %) as a white solid. NMR data: 'H-NMR (DMSO-d6, 250 MHz) 5 = 7.84 (1H, d, J=6 Hz), 8.53 (1H, d, J=6 Hz), 9.08(lH,s)ppm. Method B A suspension of 3,N-dihydroxy-isonicotinamide (168 g; 1.09 mol) in pyridine (1600 mL) that had been vigorously stirred for 15 min. to ensure an even suspension, was cooled on an ice-bath to 5 °C. Thionylchloride (241 g; 2.03 mol) was added dropwise over 1 hour whilst maintaining the temperature below 10 °C and the reaction was checked for unreacted starting material by means of the hydroxamic acid test (5 % FeCl3 in 1M HC1 was added to a reaction sample in ethanol, a magenta colour was produced if hydroxamic acid was present). After the addition was complete the cooling bath was removed and the reaction was allowed to warm up to ambient temperature over 1 hour. The reaction mixture was poured into 2 kg of ice/water with vigorous stirring and the pH was adjusted to 3 with concentrated aqueous hydrochloric acid (ca. 1.1 L, 10 M). The title compound crystallized out and the mixture was stirred on an ice-bath for 2 hours. The mixture was filtered and the residue was washed with water, ethanol and diethyl ether and dried under reduced pressure at 60 °C overnight to give isoxazolo[5,4-c]pyridin-3-ol (123 g, 83 %; HPLC purity 98 %) as a white solid. NMR data: 'H-NMR (DMSO-d6, 250 MHz) 8 = 7.84 (1H, d, J=6 Hz), 8.53 (1H, d, J=6 Hz), 9.08(lH,s)ppm. water. The combined filtrates were evaporated under reduced pressure until all of the ethanol had evaporated. A solid began to precipitate, and so the mixture was cooled in an ice-water bath with stirring for 30 min. The solution was filtered, and the residue was washed with cold water. The residue was dried to give 6-benzyl-4,5,6,7-tetrahydro-isoxazolo[5,4-c]pyridin-3-ol (48.6 g, 70%; HPLC 94% pure) as a yellowish solid. After some further evaporation of the combined mother liquors, a second crop gave a further 10.3 g (HPLC: 97.7% pure). NMR data: 'H-NMR (DMSO-d6, 500 MHz) 8 = 2.3 (2H, t, J=6 Hz), 2.67 (2H, t, J=6 Hz), 3.45 (2H, s), 3.7 (2H, s), 7.2-7.4 (5H, m), 11.3 (1H, bs) ppm. 4,5,6,7-Tetrahydro-isoxazolo[5,4-c]pyridin-3-ol hydrobromide Method A To a stirred solution of 6-benzyl-4,5,6,7-tetrahydro-isoxazolo[5,4-c]pyridin-3-ol (11.5 g, 50 mmol) and DMAP (0.61 g, 5 mmol) in ethyl acetate (100 mL) under a nitrogen atmosphere was added a solution of (Boc)2O (16.4 g, 75 mmol) in ethyl acetate (20 mL). After 30 min was added DIPEA (4.35 mL, 25 mmol) and methyl chloroformate (7.73 mL, 100 mmol), and the mixture was stirred for 48 h. the mixture was cooled in an ice-water bath, and an aqueous solution of ammonia (25% w/v, 120 mL) was added. After 15 minutes the aqueous phase was separated, and was adjusted to pH 1.0 by the addition of aqueous hydrochloric acid (10 M). This aqueous phase was extracted twice with ethyl acetate, and these ccombined extracts were dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was dissolved in a solution of gaseous HBr in acetic acid (33% w/v, 30 mL), and the mixture was stirred at 40 °C for 6 hours. The mixture was then cooled in an ice-water bath, and ethanol (90 mL) was added. A precipitate formed, and the mixture was stirred in the cold for a further 1 h. The mixture was filtered, and the reside was washed with cold ethanol and dried to give 4,5,6,7-tetrahydro-isoxazolo[5,4-c]pyridin-3-ol hydrobromide (6.4 g, 58%; HPLC >99% pure) as a white solid. Method B To a stirred solution of 6-benzyl-4,5,6,7-tetrahydro-isoxazolo[5,4-c]pyridin-3-ol (2.3 g, 10 mmol) in ethyl acetate (25 mL) under a nitrogen atmosphere was added DIPEA (2.6 mL, 15 mmol) and methyl chloroformate (2.7 mL, 35 mmol), and the mixture was stirred for 48 h. the mixture was cooled in an ice-water bath, and an aqueous solution of ammonia (25 % w/v, 30 mL) was added. After 15 minutes the aqueous phase was separated, and was adjusted to pH 1.0 by the addition of aqueous hydrochloric acid (10 M). This aqueous phase was extracted twice with ethyl acetate, and these ccombined extracts were dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was dissolved in a solution of gaseous HBr in acetic acid (33% w/v, 6.3 mL), and the mixture was stirred at 40 °C for 6 hours. The mixture was then cooled in an ice-water bath, and ethanol (25 mL) was added. A precipitate formed, and the mixture was stirred in the cold for a further i h. The mixture was filtered, and the reside was washed with cold ethanol and dried to give 4,5,6,7-tetrahydro-isoxazolo[5,4-c]pyridm-3-ol hydrobromide (1.35 g, 58 %; HPLC >99 % pure) as a white solid. A further crop gave a further 0.15 g, bringing the total yield up to 68 % (HPLC: >99%pure). NMR data: 'H-NMR (DMSO-d6, 500 MHz) 8 = 2.6 (2H, t, J=6 Hz), 3.35 (2H, t, J=6 Hz), 4.3 (2H, s), 9.5 (ca. 2H, bs), ca. 11.6 (ca. 1H, bs) ppm. (12) reacting the mixture of (7c) and (7d) with a nucleophile, followed by acidification, to obtain a compound of formula (8b) wherein W, U\ and R are as defined above, e2) reacting a compound of formula (8b) with an acid to obtain THIP as an acid addition salt. 21. The method of claim 20 wherein step a) is carried out in a polar solvent, such as NMP. 22. The method of any one of claims 20-21, step a), wherein in the alkylating agent of formula (3) R2 and R3 are independently selected from H, methyl, ethyl, allyl, phenacyl, phenyl, methoxyphenyl and L is selected from Br, Cl, I, OMs, or OTs. 23. The method of claim 22, wherein the alkylating agent of formula (3) is selected from Mel, EtI, BzBr,/>-CH3OC6H4CH2Br> allylBr, and the corresponding mesylates (OMs) and tosylates (OTs). 24. The method of any one of claims 20-23 wherein the reduction in step b) is carried out in alcohol and water, such as aqueous ethanol, 25. The method of any one of claims 20-24 wherein the mild reducing agent in step b) is LiBH4orNaBH4. 26. The method of any one of claims 20-25, step c2)4 wherein in the reagent of formula (6b) R is C|.6alkyl, C2.6alkenyl, C3.8cycloalkyl, C3_8cycloalkenyl, acyl, or phenyl optionally substituted with a C,.6alkyl, Ci.6alkoxy, or phenyl, U is N or CR1, wherein R1 is H, C^alkyl, C2-6alkenyl, C3.8cycloalkyl, C3.8cycloalkenyl, acyl, or phenyl optionally substituted with a Ci.6alkyl, C^alkoxy, or phenyl, W is O, S or NR4, wherein R4 is H, C^aHcyl, C2.6alkenyl, C3.gcycloalkyl, C3.scycloalkenyl, acyl, or phenyl optionally substituted with a Ci.6alkyl, Cj.6alkoxy, or phenyl. 27. The method of any one of claims 20-26, step c2), wherein the nucleophile is selected from Cl\ Br\ I, or NC-S". 28. The method of any one of claims 26-27, step c2), wherein the reagent of formula (6b) is selected from an isocyanate such as isopropyl isocyanate or phenyl isocyanate, or an isothiocyanate such as phenyl isothiocyanate, or a ketene. 29. The method of claim 20, step c2), wherein a compound of formula (5) is first protected as a carbonate or carbamate, such as a /-butyl- or 2,2,2-trichloroethylcarbonate/carbamate, and then reacted with the reagent of formula (6b). 30. The method of any one of claims 20-29, step d2), wherein the nucleophile, is a soft nucleophile, such as aqueous ammonia, an amine or diamine (such as methylamine, ethylenediamine), thiols, thiolates, sulfides, in an aqueous or organic solution. 31. The method of any one of claims 20-30, step d2), wherein the reaction with a nucleophile is followed by acidification by adjusting pH to 32. The method of any one of claims 20-31, wherein step d2) after reaction with the nucleophile in an aqueous solution is followed by separating the aqueous phase, followed by acidification with an aqueous acid, and extraction into an organic phase. 33. The method of any one of claims 20-32, wherein a compound of formula (8b) or a salt thereof is purified by the process of extraction from one phase to another. 34. The method of any one of claims 20-33, wherein a compound of formula (8b) is obtained in high purity, more than 98%, preferably greater than 99% according to HPLC. 35. The method of any one of claims 20-34, wherein step e2) is carried out using a mineral acid. 36. A method of preparing THIP comprising reacting a compound of formula (8b) or a salt thereof WE CLAIM: 1. A method of preparing THIP comprising the steps: a) reacting a compound of formula (2) with an alkylating agent of formula (3) wherein R2 and R3 are independently selected from H, C1-12 alkyl, C2-12alkenyl, C3-5cycloalkyl, C3.gcycloalkenyl, acyl, aryl, or heteroaryl, optionally substituted with a C1-12alkyl, C1-. 12alkoxy, or aryl, and L is a leaving group, to obtain a quarternary salt of formula (4) wherein L, R2 and R3 are as defined above, b) reacting the quarternary salt of (4) with a mild reducing agent to obtain a compound of formula (5) wherein R2 and R3 are as defined above, c) reacting a compound of formula (5) with a reagent of formula (6a) wherein R' is C3-12 alkyl, C2-12alkenyl, C3.8cycloalkyl, C3-.8cycloalkenyl, acyl, or aryl optionally substituted with one or more C1-12 alkyl, C1-12 alkoxy, or aryl, X is a leaving group, Y is O or S, ZisO, S orC1-.6alkyl, optionally followed by reaction with a nucleophile, to obtain a mixture of a compound of formula (7a) and a compound of (7b) wherein Y, Z, and R' are as defined above, d) reacting the mixture of (7a) and (7b) with a nucleophile, followed by acidification, to obtain a compound of formula (8a) wherein Y, Z, and R' are as defined above, e) reacting a compound of formula (8a) with an acid to obtain THIP as an acid addition salt. 2. The method of claim 1 wherein step a) is carried out in a polar solvent, such as NMP. 3. The method of any one of claims 1-2, step a), wherein in the alkylating agent of formula (3) R2 and R3 are independently selected from H, methyl, ethyl, ally], phenacyl, phenyl, methoxyphenyl and L is selected from Br, Cl, I, OMs, or OTs. 4. The method of claim 3, wherein the alkylating agent of formula (3) is selected from Mel, EtI, BzBr, p-CH3OC6C6H4CH2zBr, allylBr, and the corresponding mesylates (OMs) and tosylates (OTs). 5. The method of any one of claims 1-4 wherein the reduction in step b) is carried out in alcohol and water, such as aqueous ethanol. 6. The method of any one of claims 1-5 wherein the mild reducing agent in step b) is LiBH4 or NaBH4. 7. The method of any one of claims 1-6, step c), wherein in the reagent of formula (6a) R' is C1-12alkyl, C].]2alkenyl, C3.8cycloalkyl, C3.8cycloalkenyl, acyl, or aryl optionally substituted with a C1-12alkyl, C1-12alkoxy, or aryl, X is selected from Cl, Br, I, Y is O, or S Z is O, or S. 8. The method of claim 7, step c), wherein the reagent of formula (6a) is selected from C1_ 12alkyl chloroformate, such as methyl chloroformate, ethyl chloroformate, or ethyl chlorothiolformate. 9. The method of claim 1, step c), wherein a compound of formula (5) is first protected as a carbonate or carbamate, such as a /-butyl- or 2,2,2-trichloroethylcarbonate/carbarnate, and then reacted with the reagent of formula (6a). 10. The method of any one of claims 1-9, step d), wherein the nucleophile is a soft nucleophile, such as aqueous ammonia, an amine or diamine (such as methylamine, ethylenediamine), thiols, thiolates, sulfides, in an aqueous or organic solution. 11. The method of any one of claims 1-10, step d), wherein the reaction with a nucleophile is followed by acidification by adjusting pH to ≤5. 12. The method of any one of claims 1-11, wherein step d) after reaction with the nucleophile in an aqueous solution is followed by separating the aqueous phase, followed by acidification with an aqueous acid, and extraction into an organic phase. 13. The method of any one of claims 1-12, wherein a compound of formula (8a) or a salt thereof is purified by a process of extraction from one phase to another. 14. The method of any one of claims 1-13, wherein a compound of formula (8a) is obtained in high purity, more than 98%, preferably greater than 99% according to HPLC. 15. The method of any one of claims 1-14, wherein step e) is carried out using a mineral acid. 16. A method of preparing a compound of formula (2) comprising reacting the compound of formula (10) with a dehydrating agent, to obtain compound of formula (2). 17. A compound of formula (2) or a salt thereof. 18. A method of preparing THIP comprising reacting a compound of formula (8a) or a salt thereof wherein R' is C1.12alkyl, C2.]2alkenyl, C3.8cycloalkyl, C3.Bcycloalkenyl, acyl, or aryl optionally substituted with one or more C1-12 alkyl, C1-12 alkoxy, or aryl, Y is O or S, and Z is O, S or C1-.6alkylene, with an acid, typically a mineral acid, to obtain THIP as an acid addition salt. 19. A compound of formula (8a) wherein R' is C1-12 alkyI> C1-12 alkenyI, C3.8cycloalkyl, C3-8cycloalkenyl, acyl, or aryl optionally substituted with one or more C1-12 alkyi, C1-12 alkoxy, or aryl, Y is O or S, Z is O, S or C1.6alkyl, or a salt thereof. 20. A method of preparing THIP comprising the steps: a) reacting a compound of formula (2) with an alkylating agent of formula (3) wherein R2 and R3 are independently selected from H, C1-,.12alkyl, C2_12alkenyl, C3.gcycloalkyl, C3.Rcycloalkenyl, acyl, aryl, or heteroaryl, optionally substituted with a C1-12 alkyl, C1- 12alkoxy, or aryl, and L is a leaving group, to obtain a quarternary salt of formula (4) wherein L, R2 and R3 are as defined above, b) reacting the quarternary salt of (4) with a mild reducing agent to obtain a compound of formula (5) wherein R2 and R3 are as defined above, c2) reacting a compound of formula (5) with a reagent of formula (6b) wherein R is C1-12 alkyl, C2-12alkenyl, C3-8cycloalkyl, C3.8cycloalkenyl, acyl, or aryl optionally substituted with one or more C1.12alkyl, C1-12 alkoxy, or aryl, U is N or CR1, wherein Rl is H, or R, W is O, S or NR\ wherein R4 is H, or R, optionally followed by reaction with a nucleophile, to obtain a mixture of a compound of formula (7c) and a compound of (7d) wherein R is C1-12 alkyl, C2.12alkenyl, C3.8cycloalkyl, C3-8 .acycloalkenyl, acyl, or aryl optionally substituted with one or more C1,.12alkyl, C1-12 alkoxy, or aryl, U' is N or CR1, wherein R1 is H, or R, W is O, S or NR4, wherein R4 is H, or R, (12) reacting the mixture of (7c) and (7d) with a nucleophile, followed by acidification, to obtain a compound of formula (8b) wherein W, U' and R are as defined above, e2) reacting a compound of formula (8b) with an acid to obtain THIP as an acid addition salt. 21. The method of claim 20 wherein step a) is carried out in a polar solvent, such as NMP. 22. The method of any one of claims 20-21, step a), wherein in the alkylating agent of formula (3) R2 and R3 are independently selected from H, methyl, ethyl, allyl, phenacyl, phenyl, methoxyphenyl and L is selected from Br, Cl, I, OMs, or OTs. 23. The method of claim 22, wherein the alkylating agent of formula (3) is selected from Mel, EtI, BzBr,p--CH3OC6H4CH2Br> allylBr, and the corresponding mesylates (OMs) and tosylates (OTs). 24. The method of any one of claims 20-23 wherein the reduction in step b) is carried out in alcohol and water, such as aqueous ethanol, 25. The method of any one of claims 20-24 wherein the mild reducing agent in step b) is LiBH4orNaBH4. 26. The method of any one of claims 20-25, step c2)4 wherein in the reagent of formula (6b) R is C|.6alkyl, C2.6alkenyl, C3.8cycloalkyl, C3_8cycloalkenyl, acyl, or phenyl optionally substituted with a C1-.6alkyl, C1.6alkoxy, or phenyl, U is N or CR1, wherein R1 is H, C1-6 alkyl, C2-6alkenyl, C3.8cycloalkyl, C3.8cycloalkenyl, acyl, or phenyl optionally substituted with a C1-.6alkyl, C^alkoxy, or phenyl, W is O, S or NR4, wherein R4 is H, C1-6 aHcyl, C2.6alkenyl, C3.8cycloalkyl, C3.8cycloalkenyl, acyl, or phenyl optionally substituted with a C1-.6alkyl, C1-.6alkoxy, or phenyl. 27. The method of any one of claims 20-26, step c2), wherein the nucleophile is selected from Cl\ Br\ I, or NC-S". 28. The method of any one of claims 26-27, step c2), wherein the reagent of formula (6b) is selected from an isocyanate such as isopropyl isocyanate or phenyl isocyanate, or an isothiocyanate such as phenyl isothiocyanate, or a ketene. 29. The method of claim 20, step c2), wherein a compound of formula (5) is first protected as a carbonate or carbamate, such as a /-butyl- or 2,2,2-trichloroethylcarbonate/carbamate, and then reacted with the reagent of formula (6b). 30. The method of any one of claims 20-29, step d2), wherein the nucleophile, is a soft nucleophile, such as aqueous ammonia, an amine or diamine (such as methylamine, ethylenediamine), thiols, thiolates, sulfides, in an aqueous or organic solution. 31. The method of any one of claims 20-30, step d2), wherein the reaction with a nucleophile is followed by acidification by adjusting pH to ≤5. 32. The method of any one of claims 20-31, wherein step d2) after reaction with the nucleophile in an aqueous solution is followed by separating the aqueous phase, followed by acidification with an aqueous acid, and extraction into an organic phase. 33. The method of any one of claims 20-32, wherein a compound of formula (8b) or a salt thereof is purified by the process of extraction from one phase to another. 34. The method of any one of claims 20-33, wherein a compound of formula (8b) is obtained in high purity, more than 98%, preferably greater than 99% according to HPLC. 35. The method of any one of claims 20-34, wherein step e2) is carried out using a mineral acid. 36. A method of preparing THIP comprising reacting a compound of formula (8b) or a salt thereof wherein, R isC1-12 alkyl, C2.12alkenyl, C3.8cycloalkyl, C3.8cycloalkenyl, acyl, or aryl optionally substituted with one or more C1-12alkyl, C1-12 alkoxy) or aryl, U' is NH or CHR\ wherein R1 is H, or R, W is 0, S or NR4, wherein R4 is H, or R, with an acid, typically a mineral acid, to obtain THIP as an acid addition salt. 37. A compound of formula (8b) wherein, R is C1-12alkyl, C2.12alkenyl, C3.8cycloalkyl, C3.8cycloalkenyl, acyl, or aryl optionally substituted with one or more C1.12alkyl, C1-12 alkoxy, or aryl, U' is NH or CHR1, wherein R1 is H, or R, W is O, S or NR4, wherein R4 is H, or R, or a salt thereof. |
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779-chenp-2006 amended claims 10-06-2011.pdf
779-CHENP-2006 OTHER PATENT DOCUMENT 24-02-2011.pdf
779-CHENP-2006 AMENDED CLAIMS 24-02-2011.pdf
779-CHENP-2006 AMENDED PAGES OF SPECIFICATION 24-02-2011.pdf
779-CHENP-2006 CORRESPONDENCE OTHERS 16-07-2010.pdf
779-chenp-2006 correspondence others 10-06-2011.pdf
779-CHENP-2006 CORRESPONDENCE OTHERS.pdf
779-CHENP-2006 CORRESPONDENCE PO.pdf
779-CHENP-2006 EXAMINATION REPORT REPLY RECIEVED 24-02-2011.pdf
779-chenp-2006 form-3 24-02-2011.pdf
779-CHENP-2006 POWER OF ATTORNEY 24-02-2011.pdf
779-chenp-2006-correspondence-others.pdf
779-chenp-2006-description(complete).pdf
Patent Number | 248699 | ||||||||||||
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Indian Patent Application Number | 779/CHENP/2006 | ||||||||||||
PG Journal Number | 32/2011 | ||||||||||||
Publication Date | 12-Aug-2011 | ||||||||||||
Grant Date | 05-Aug-2011 | ||||||||||||
Date of Filing | 03-Mar-2006 | ||||||||||||
Name of Patentee | H. LUNDBECK A/S | ||||||||||||
Applicant Address | 9, OTTILIAVEJ, DK-2500 VALBY-COPENHAGEN, DENMARK | ||||||||||||
Inventors:
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PCT International Classification Number | C07S 498/04 | ||||||||||||
PCT International Application Number | PCT/DK04/00579 | ||||||||||||
PCT International Filing date | 2004-09-01 | ||||||||||||
PCT Conventions:
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