Process for the steroselective preparation of chiral 2- [(hetero)arylalkylsulfanyl] pyrimidines and products obtainable therefrom
11542281 · 2023-01-03
Assignee
Inventors
Cpc classification
International classification
Abstract
Described herein is a process for the preparation of a compound of Formula I, ##STR00001##
wherein R.sup.1 and R.sup.2 each have the meanings provided in the description. Also described is a process for the preparation of pharmaceutically-active compounds including the process for the preparation of compounds of Formula I.
Claims
1. A process for the preparation of a compound of formula I, ##STR00030## or a salt thereof, wherein R.sup.1 represents aryl or pyridyl optionally substituted with one or more groups selected from halo, —CN, —C(O)NR.sup.3R.sup.4, —S(O).sub.2R.sup.5; C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, wherein the latter three groups are optionally substituted by one or more F; R.sup.2 represents C.sub.1-6 alkyl optionally substituted by one or more F; R.sup.3 and R.sup.4 each independently represent H or C.sub.1-6 alkyl optionally substituted by one or more F; R.sup.5 represents C.sub.1-6 alkyl optionally substituted by one or more F; which process comprises the steps of: (i) forming a compound of formula II, ##STR00031## wherein R.sup.1 and R.sup.2 are as defined for a compound of formula I and R.sup.6 represents C.sub.1-6 alkyl optionally substituted by one or more F, or phenyl optionally substituted by one or more groups selected from halo, methyl and —NO.sub.2; by reacting a compound of formula III ##STR00032## wherein R.sup.1 and R.sup.2 are as defined for a compound of formula I or II; with a suitable sulfonating agent in the presence of a suitable base B.sup.1 and a suitable solvent S.sup.1, and subsequently (ii) reacting the compound of formula II, with a compound of formula IV, ##STR00033## wherein M.sup.+ represents Li.sup.+, Na.sup.+, K.sup.+ or Cs.sup.+ wherein the compound of formula III is provided as a single enantiomer.
2. The process as claimed in claim 1, wherein the compound of formula II is not isolated from the reaction mixture from step (i) before it is used in step (ii).
3. The process as claimed in claim 1, wherein S.sup.1 is a solvent in which the salt formed between B.sup.1 and the leaving group of the sulfonating agent is insoluble.
4. The process as claimed in claim 1, wherein step (ii) comprises bringing a solution of a compound of formula II in a suitable solvent S.sup.1 into association with a solution of a compound of formula IV in a suitable solvent S.sup.2.
5. The process as claimed in claim 4, wherein S.sup.2 is a polar aprotic solvent.
6. The process as claimed in claim 4, wherein S.sup.2 is N,N-dimethylformamide.
7. The process as claimed in claim 1, wherein the process further comprises the step of: (iii) preparing a compound of formula IV by reacting a compound of formula V ##STR00034## with a suitable base B.sup.2 in the presence of a suitable solvent S.sup.2, optionally wherein the solution of a compound of formula IV is obtained from step (iii), after one or more purification steps.
8. The process as claimed in claim 7, wherein B.sup.2 is selected from the group consisting of lithium hydroxide, lithium carbonate, sodium hydroxide, sodium carbonate, potassium hydroxide, potassium carbonate, caesium hydroxide and caesium carbonate.
9. The process as claimed in claim 7, wherein B.sup.2 is sodium hydroxide.
10. The process as claimed in claim 1, wherein S.sup.1 is selected from the group consisting of diethyl ether, methyl tert-butyl ether, 1,2-dimethoxyethane, 1,4-dioxane, tetrahydrofuran and 2-methyltetrahydrofuran.
11. The process as claimed in claim 1, wherein B.sup.1 is an organic amine base.
12. The process as claimed in claim 1, wherein R.sup.1 represents aryl or pyridyl optionally substituted with one or more groups selected from halo, —CN, —SO.sub.2Me, or —CONH.sub.2.
13. The process as claimed in claim 1, wherein R.sup.2 represents C.sub.1-3 alkyl.
14. The process as claimed in claim 1, wherein the process further comprises the step of: (ib) removal of the salt formed between B.sup.1 and the leaving group of the sulfonating agent from the solution of a compound of formula II in S.sup.1 obtained from step (i).
15. The process as claimed in claim 1, further comprising the step of: (iv) treating the crude material obtained from step (ii) with a suitable solvent S.sup.4 to cause precipitation of the compound of formula I, optionally wherein S.sup.4 is acetonitrile.
16. The process as claimed in claim 1, wherein the sulfonating agent is mesyl chloride or tosyl chloride.
17. The process as claimed in claim 1, wherein the process is a process for the preparation of a compound of formula Ia, or a salt thereof, ##STR00035## wherein R.sup.1 represents aryl or pyridyl optionally substituted with one or more groups selected from halo, —CN, —C(O)NR.sup.3R.sup.4, —S(O).sub.2R.sup.5; C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, wherein the latter three groups are optionally substituted by one or more F, and R.sup.2 represents C.sub.1-6 alkyl optionally substituted by one or more F.
18. The process as claimed in claim 17, wherein the compound of formula Ia is 6-amino-2-{[(1S)-1-phenylethyl]sulfanyl}pyrimidin-4-ol, or a salt thereof ##STR00036##
19. The process as claimed in claim 17, wherein the compound of formula Ia has a chiral purity of greater than 96%.
20. The process as claimed in claim 1, wherein S.sup.1 is methyl tert-butyl ether.
21. The process as claimed in claim 1, wherein B.sup.1 is triethylamine.
22. The process as claimed in claim 1, wherein R.sup.1 represents phenyl.
23. A process as claimed in claim 1, wherein R.sup.2 represents methyl.
Description
BRIEF DESCRIPTION OF THE FIGURES
(1)
(2)
EXAMPLES
(3) Abbreviations
(4) DIPEA N,N-diisopropylethylamine
(5) DMF N,N-dimethylformamide
(6) HPLC high pressure liquid chromatography
(7) MEK methyl ethyl ketone
(8) MTBE methyl tert-butyl ether
(9) NMP N-methyl-2-pyrrolidone
(10) NMR nuclear magnetic resonance
(11) MS mass spectrometry
Example 1
Preparation of 6-amino-2-{[(1S)-1-phenylethyl]sulfanyl}pyrimidin-4-ol (1)
(12) ##STR00023##
(13) Generation of Thiolate Anion:
(14) A 250 mL roundbottomed flask was charged with NaOH flakes (600 mg, 15.00 mmol), 6-amino-2-thioxo-1H-pyrimidin-4-one (Ark Pharm, 95+%, 2.37 g, 15.75 mmol) and DMF (30 mL). The flask was fitted with a condenser. The mixture was stirred at 65° C. (start 13:25). After 1 h 30 min the mixture was allowed to cool down to RT and NaBH.sub.4 (174 mg, 4.50 mmol, 30%) was added (15:10) in order to reduce any disulfide formed. The mixture was stirred at RT for 1 h 50 min.
(15) Generation of Mesylate:
(16) In parallel with the reaction described above (R)-1-phenylethyl mesylate in MTBE was prepared as follows:
(17) To a stirred solution of (R)-1-phenylethanol (Ark Pharm, 98%, 1.87 g, 15.00 mmol) and triethylamine (Aldrich, 99.5%, 1.60 g, 15.75 mmol) in MTBE (15 mL) was added dropwise, over 14 min, at ice-bath temperature, a solution of mesyl chloride (Lancaster, 98%, 1.84 g, 15.75 mmol) in MTBE (10 mL). The mixture was stirred at ice-bath temperature for 20 min. The formed Et.sub.3NHCl salt was filtered off and the filter cake was washed with ca. 10 mL MTBE. The MTBE solution was concentrated to ca. 10 mL.
(18) Alkylation Step:
(19) The MTBE solution containing the mesylate was added dropwise to the DMF solution containing the 6-amino-2-thioxo-1H-pyrimidin-4-one anion over 10 min at ice-bath temperature (17:10). The mixture was allowed to slowly warm up to RT and was stirred at RT overnight. Work up after 17.5 h: The mixture was concentrated to a small volume. EtOAc (ca. 50 mL) was added, which resulted in heavy precipitation of 6-amino-2-thioxo-1H-pyrimidin-4-one. The mixture was sonicated by ultrasound and then the solid was filtered off and the filter cake was washed with EtOAc (ca. 10 mL). The solid was suspended in sat. NaHCO.sub.3 (15 mL) and EtOAc (20 mL) was added. The resulting suspension was sonicated and filtered down into a separatory funnel. The phases were separated and the aqueous phase was discarded. The organic phase containing product was combined with the EtOAc filtrate. The combined organic phases were washed with sat. NaHCO.sub.3 (10 mL), dried over MgSO.sub.4, filtered and evaporated. The last residue of DMF was distilled off (78° C./18 mbar) to yield 4.38 g of crude product as a light yellow viscous oil. CH.sub.3CN (11 mL) was added to the oil and the resulting solution was ultrasound sonicated and heavy precipitation was observed after a few minutes. The mixture was digested at 75° C. for 45 min. The mixture was allowed to slowly cool down to RT and the solid was collected by filtration and was washed with ice-cold CH.sub.3CN (ca. 5 mL). The resulting white solid material was dried in a vacuum oven at 40° C. for 2.5 days. Yield: 1.861 g. .sup.1H NMR (600 MHz, CD.sub.3OD) δ ppm 7.43-7.47 (m, 2H) 7.31-7.35 (m, 2H) 7.23-7.28 (m, 1H), 5.12 (q, J=7.1 Hz, 1H) 5.06 (s, 1H) 1.75 (d, J=7.0 Hz, 3H). MS (ESI+) m/z 248 [M+H].sup.+.
(20) HPLC purity: ca. 94%
(21) HPLC chiral purity: 99.7% (S), i.e. 99.4% e.e. The chiral HPLC trace is reproduced in
(22) Measured on an Astec CHIROBIOTIC T column (250×4.6 mm, 5 μm), Eluent: 100% MeOH, Agilent 1100 system.
(23) .sup.1H NMR: appears pure, except for some residual solvent (MeCN: 0.03% (w/w), DMF: 0.16% (w/w))
Example 2
Preparation of 6-amino-2-{[(1S)-1-phenylethyl]sulfanyl}pyrimidin-4-ol (1) (50 mmol scale)
(24) ##STR00024##
(25) Generation of Thiolate Anion:
(26) A 250 mL round-bottomed flask was charged with NaOH flakes (2.00 g, 50.00 mmol), 6-amino-2-thioxo-1H-pyrimidin-4-one (Ark Pharm, 95+%, 7.91 g, 52.50 mmol) and DMF (100 mL). The flask was fitted with a condenser. The mixture was stirred at 65° C. (start 11:00). After 2 h 30 min the mixture was allowed to cool down to RT and NaBH.sub.4 (567 mg, 15.00 mmol, 30%) was added (14:10) in order to reduce any disulfide formed. The mixture was stirred at RT for 40 min.
(27) Generation of Mesylate:
(28) In parallel with the reaction described above (R)-1-phenylethyl mesylate in MTBE was prepared as follows:
(29) To a stirred solution of (R)-1-phenylethanol (Ark Pharm, 98%, 6.23 g, 50.00 mmol) and triethylamine (Aldrich, 99.5%, 5.34 g, 52.50 mmol) in MTBE (50 mL) was added dropwise, over 10 min, at ice-bath temperature, a solution of mesyl chloride (Lancaster, 98%, 6.14 g, 52.50 mmol) in MTBE (30 mL). The mixture was stirred at ice-bath temperature for 20 min. The formed Et.sub.3NHCl salt was filtered off and the filter cake was washed with ca. 20 mL MTBE. The MTBE solution was concentrated to ca. 25 mL.
(30) Alkylation Step:
(31) The MTBE solution containing the mesylate was added dropwise to the DMF solution containing the 6-amino-2-thioxo-1H-pyrimidin-4-one anion over 20 min at ice-bath temperature (15:05). The mixture was allowed to slowly warm up to RT and was stirred at RT overnight. Work up after 19 h: The mixture was concentrated to a small volume, so that almost all of the DMF was removed. EtOAc (120 mL) was added, which resulted in heavy precipitation of 6-amino-2-thioxo-1H-pyrimidin-4-one. The mixture was sonicated by ultrasound and then the solid was filtered off and the filter cake was washed with EtOAc (ca. 30 mL). The solid was suspended in sat. Na.sub.2CO.sub.3 (50 mL) and EtOAc (70 mL) was added. The resulting suspension was stirred until all of the material was dissolved, and it was then transferred to a separatory funnel. The phases were separated and the aqueous phase was discarded. The organic phase containing product was combined with the EtOAc filtrate. The combined organic phases were washed with sat. NaHCO.sub.3 (25 mL), water (15 mL), brine (15 mL), dried over MgSO.sub.4, filtered and evaporated. The last residue of DMF was distilled off (78° C.118 mbar) to yield 13.32 g of crude product as a light yellow semi solid. CH.sub.3CN (35 mL) was added to the crude material and the resulting suspension was ultrasound sonicated. The mixture was digested at 75° C. for 30 min. The mixture was allowed to slowly cool down to RT and the solid was collected by filtration and was washed with ice-cold CH.sub.3CN (ca. 10 mL). The resulting white solid material was dried in a vacuum oven at 40° C. for 2 days. Yield: 6.168 g (50%) of product as a white solid. .sup.1H NMR (600 MHz, CD.sub.3OD) δ ppm 7.43-7.47 (m, 2H) 7.31-7.35 (m, 2H) 7.23-7.28 (m, 1H), 5.13 (q, J=7.0 Hz, 1H) 5.06 (s, 1H) 1.75 (d, J=7.0 Hz, 3H). MS (ESI+) m/z 248 [M+H].sup.+.
(32) HPLC purity: 96.5%
(33) HPLC chiral purity: 99.8% (S), i.e. 99.6% e.e. (The peak corresponding to the R-isomer can hardly be detected. The integral is uncertain, due to the baseline noise). The chiral HPLC trace is reproduced in
(34) Measured on an Astec CHIROBIOTIC T column (250×4.6 mm, 5 μm), Eluent: 100% MeOH, Agilent 1100 system.
(35) .sup.1H NMR: Appears pure except for some residual solvent (MeCN: 0.41% (w/w) DMF: 0.23% (w/w)).
Example 3
Preparation of (2R)-2-[(2-amino-5-{[(1S)-1-phenylethyl]thio}[1,3]thiazolo[4,5-d]pyrimidin-7-yl)amino]-4-methylpentan-1-ol.HCl
(36) 3.1 Preparation of 4-amino-6-hydroxy-2-{[(1S)-1-phenylethyl]sulfanyl}pyrimidin-5-yl thiocyanate (2)
(37) ##STR00025##
(38) Compound 1 (1.63 g, 6.59 mmol) and KSCN (1.92 g, 19.8 mmol) were dissolved in DMF (20 mL) in a 100 mL flask. The mixture was heated to 65° C. until all of the starting material had dissolved. Pyridine (886 mg, 12.35 mmol) in DMF (2 mL) was added. The reaction mixture was cooled to 4° C. and bromine (1.219 g, 7.62 mmol) in DMF (3 mL) was added dropwise (15:12) over 10 min leading to some precipitation. The mixture was stirred at 4-10° C. for 1 h 15 min when HPLC indicated complete conversion to product. The reaction was allowed to warm up to RT and 5 mL of 15% Na.sub.2S.sub.2O.sub.5 (sodium metabisulfite) was added together with water (2 mL). The mixture was stirred at 60° C. for 10 min. Then at RT more water (25 mL) was added. Stir at RT overnight. The solid product was collected by filtration, washed with cold water and dried for 4.5 h in vacuum at 60° C. Yield: 1.806 g (90%) of 98% pure product as a light yellow solid. 1H NMR (600 MHz, CD.sub.3OD) δ ppm 7.44-7.48 (m, 2H) 7.32-7.36 (m, 2H) 7.25-7.29 (m, 1H) 5.14 (q, J=7.1 Hz, 1H) 1.77 (d, J=7.3 Hz, 3H). MS (ESI+) m/z 305 [M+H].sup.+.
(39) .sup.1H NMR: appears very pure. The only visible contamination is DMF (ca. 0.36% w/w) 3.2 Preparation of 2-amino-5-{[(1S)-1-phenylethyl]sulfanyl}[1,3]thiazolo[4,5-d]pyrimidin-7-ol (3)
(40) ##STR00026##
(41) Compound 2 (1.80 g, 5.91 mmol was slurried in DMF (16 mL) and 2M NaOH (6 mL, 12 mmol) was added dropwise at RT. The mixture turned red-brown upon addition of NaOH and the slurry was dissolved. Heat to 120° C. (13:20) (HPLC after 3 h: 100% conversion to product).
(42) Work up: The mixture was allowed to cool to RT, and water (20 mL) was added=>slight precipitation. The pH of the reaction mixture was adjusted to ca. pH 4-5 by addition of conc. HCl. The solid was collected by filtration and washed with two portions of water (2×8 mL) and dried in vacuum at 60° C. to yield 1.687 g (94%) of product as an off-white solid. 1H NMR (600 MHz, CD3OD) δ ppm 7.45-7.49 (m, 2H) 7.31-7.35 (m, 2H) 7.24-7.28 (m, 1H) 5.21 (q, J=7.1 Hz, 1H) 1.79 (d, J=7.0 Hz, 3H). MS (ESI+) m/z 305[M+H].sup.+.
(43) HPLC: ca. 94% purity
(44) .sup.1H NMR: Looks pure but some DMF present. Integrals indicate 0.55% (w/w).
(45) 3.3 Preparation of 7-chloro-5-{[(1S)-1-phenylethyl]sulfanyl}[1,3]thiazolo[4,5-d]pyrimidin-2-amine (4)
(46) ##STR00027##
(47) To a slurry of compound 3 (1.82 g, 5.98 mmol) in dioxane (15 mL) were added DMF (962 mg, 13.2 mmol) in dioxane (2.5 mL) and POCl.sub.3 (3.03 g, 19.7 mmol) in dioxane (2.5 mL) at RT (start: 14:00). After 30 min the slurry had dissolved into a light brown homogeneous solution. HPLC after 0.5 h at RT shows the imine formed by DMF and the starting material (68%), and imine formed by the product and DMF (32%). The reaction mixture was then heated at 65° C. (start: 13:40). HPLC after 3 h at 65° C. shows complete conversion to imine formed by DMF and the product. The reaction mixture was allowed to cool to RT and water (5 mL) was added. The temperature was raised to 65° C. (17:40). After stirring for 10 min at this temperature all of the product-imine was hydrolyzed. The mixture was cooled to RT. Water (10 mL) was added and the mixture was evaporated to about half the volume. The pH was adjusted to ca. 6-7 with sat. NaHCO.sub.3 and solid NaHCO.sub.3. The resulting phase was extracted with EtOAc (3×25 mL) and the combined organic phases were washed with sat. Na.sub.2CO.sub.3 (2×6 mL), water (6 mL) and brine (6 mL), dried over Na.sub.2SO.sub.4 and evaporated to yield 1.746 g (98%) of >97% pure product as an light orange solid. .sup.1H NMR (600 MHz, CD.sub.3OD) δ ppm 7.44-7.49 (m, 2H) 7.28-7.33 (m, 2H) 7.20-7.25 (m, 1H) 5.06 (q, J=7.1 Hz, 1H) 1.75 (d, J=7.3 Hz, 3H). MS (ESI+) m/z 323 [M+H].sup.+.
(48) .sup.1H NMR: Looks very pure, but still solvent present. DMF: 2.7% (w/w), EtOAc: 1.8% (w/w), dioxane: 1.8% (w/w).
(49) Yield corrected for solvent content: ca. 5.065 g (92%).
(50) 3.4 Preparation of (2R)-2-[(2-amino-5-{[(1S)-1-phenylethyl]thio}[1,3]thiazolo[4,5-d]pyrimidin-7-yl)amino]-4-methylpentan-1-ol.xHCl (5)
(51) ##STR00028##
(52) Compound 4 (1.852 g, 5.74 mmol), DIPEA (1.112 g, 8.61 mmol) and D-leucinol (1.008 g, 8.61 mmmol) were dissolved in NMP (12 mL) and the mixture was stirred at 120° C. in a sealed pyrex tube (start:17:40).
(53) HPLC after 15.5 h: ca. 98% conversion
(54) HPLC after 19.5 h: >99% conversion
(55) Work up: Ice water was poured into the mixture. Initially a solid was formed, but at the end of the addition the solid collapsed to a dark brown oil. EtOAc (50 mL) was added and the phases were separated. The aqueous phase was extracted with EtOAc (2×25 mL), and the combined organic phases were washed with water (8 mL), sat. NaHCO.sub.3 (3×8 mL), water (8 mL) and brine (8 mL), dried over MgSO.sub.4, filtered and evaporated. Dried in vacuum to yield 2.697 g of crude material as a brown oil. HPLC purity: ca. 92%. The oil was dissolved in MEK (ca. 18 mL) and conc. HCl (12.5 M, 574 μL, 7.18 mmol) was added.
(56) There was no spontaneous precipitation of the HCl salt. The mixture was gently stirred at RT and after ca. 20 min precipitation occurred. The mixture was stirred gently for 2.5 h and the solid was isolated by filtration on a P3 sintered glass filter. The solid was washed with three portions of MEK and was then dried in vacuum at 60° C. for 2.5 days. Yield (batch 1): 1.224 g (48.5%) of the product as hydrochloride salt.
(57) HPLC purity: 99.0% (basic method);
(58) 97.4% (acidic method).
(59) A substantial amount of solids passed through the filter into the filtrate. The solids were isolated by centrifugation and the supernatant was removed by pipette. The solid was washed with two portions (ca. 2×5 mL) of MEK. After the last supernatant was removed the product was dried in vacuum at 60° C. for 2.5 days. Yield (batch 2): 324 mg (12.8%) of the product as hydrochloride salt.
(60) HPLC purity: 99.0% (basic method);
(61) 97.5% (acidic method).
(62) Combined yield: 1.548 g (61.3%)
(63) Both batches contain ca. 0.07% DMF (w/w). The DMF was already present in the starting material.
(64) Further Purification of the Combined Batches
(65) The two batches of compound 5 were combined (1.338 g, 3.041 mmol) in a 50 mL roundbottomed flask and water (6 mL) was added followed by 2M NaOH (1.6 mL, 3.2 mmol). The mixture was stirred and EtOAc (40 mL) was added. An additional 0.5 mL (1 mmol) 2M NaOH was added during stirring. After 15 min all of the solids were dissolved and the phases were separated. The pH of the aqueous phase was measured with a pH stick=>pH=7. More 2M NaOH (0.4 mL, 0.8 mmol) was added to the aqueous phase resulting in a pH of 10. The aq. phase was extracted with EtOAc (25 mL) and the phases were separated. The combined organic phases were dried over Na.sub.2SO.sub.4, filtered and evaporated to yield the free base as a crystalline beige solid. The free base was dissolved in MEK (15 mL) and HCl (37%, 12.5 M, 255 μL, 3.19 mmol) was added during stirring. A white precipitate was immediately formed. The mixture was stirred gently for 2 h and the solid was collected by filtration on a P4 sintered glass filter. The solids were washed with MEK (5 mL) and dried in vacuum at 60° C. for 3 h. Yield: 1.187 g (89% based on the unpurified material) of 99% pure product as a white solid. .sup.1H NMR (600 MHz, CD3OD) δ ppm 7.49 (d, J=7.3 Hz, 2H) 7.37 (t, J=7.6 Hz, 2H) 7.27-7.32 (m, 1H) 5.23 (q, J=7.0 Hz, 1H) 4.60-4.70 (m, 1H) 3.55 (d, J=5.5 Hz, 2H) 1.83 (d, J=7.3 Hz, 3H) 1.67-1.76 (m, 1H) 1.58-1.65 (m, 1H) 1.48-1.54 (m, 1H) 1.00 (d, J=6.7 Hz, 3H) 0.98 (d, J=6.7 Hz, 3H). MS (ESI+) m/z 404 [M+H].sup.+
(66) The diasteromeric ratio of the final product reflects the enantiomeric ratio of the starting material (compound 1), which was 99.7% (S).
(67) .sup.1H NMR: The spectrum looks very pure. Trace amounts of DMF were, however, detected.
Comparative Example 4
Process scale two-step procedure for the synthesis of 6-amino-2-{[(1S)-1-phenylethyl]sulfanyl}pyrimidin-4-ol (1)
(68) ##STR00029##
(69) Step 1
(70) A dry 1380 L glass lined reactor was charged at Ti=20° C. with ethyl acetate and (s)-phenyl ethanol under nitrogen atmosphere. The clear to yellow solution was kept at Ti=20° C. for 30 minutes then discharged to 200 L poly lined drums. To the 1380 L glass lined reactor was charged cyanuric chloride, ethyl acetate (1.2) and N,N-dimethylformamide within 60 minutes. The solution was heated from Ti=6.3° C. to Ti=25° C. within 25 minutes then cooled to Ti=−5° C. within 180 minutes. By use of a 1″ diaphragm pump, the premade solution of (s)-phenylethanol in ethyl acetate was charged within 12 hours at a maximum Ti=−0.4° C. then kept at Ti=−5° C. for 3 hours. IPC sample indicated (s)-phenyl ethanol=0.35% (Target <1%). Propan-2-ol was charged within 120 minutes at Ti=−5° C. and kept for 30 minutes, celite was charged and then filtered on a stainless steel nutsche filter equipped with 50 μm cloth, significant filtration problems encountered due to the cloth blinding, material was recharged portion wise to a 50 L pressure filter with 50 μm cloth with celite bed. The solid was washed with ethyl acetate on portionwise filtration. Filtration liquors were recharged to the 1380 L vessel and set for distillation at maximum Ti=40.9° C. and vac 200 mbar removing 750 kg distillate. The vessel was cooled to Ti<25° C. and filtered portionwise on a 50 L pressure filter equipped with 50 μm cloth and celite bed, portionwise washing with ethyl acetate. Filtration liquors were recharged to a 330 L vessel and set for distillation at maximum Ti=35.1° C. and vac 24 mbar removing 500 kg distillate. 275 kg was isolated as a pale-yellow liquid.
(71) Result:
(72) 275 kg uncorrected:
(73) GC Purity: 73.87% (area %)
(74) GC Chiral Purity: 94.9% (area %, R Isomer).
(75) Step 2
(76) A dry 2800 L glass lined reactor was charged at Ti=20° C. with N,N-dimethylformamide, sodium hydroxide pellets and 4-Amino-6-hydroxy-2-mercapropyrimidine within 60 minutes maintaining the temperature below Ti=25° C. Heated to Ti=62.5° C. within 60 minutes and kept for 30 minutes. (1R)-phenylethyl chloride was charged within 75 minutes maintaining Ti=60-65° C. The reaction was kept at Ti=60-70° C. for 6 hours. IPC sample indicated 4-Amino-6-hydroxy-2-mercapropyrimidine=<0.1% (Target <1%). Reaction cooled to Ti<25° C. and charged water, pH adjusted to 12.01 using 32% Sodium hydroxide within 90 minutes. Charged Toluene and kept for 30 minutes followed by filtration to remove interphase solids using a stainless steel nutsche filter equipped with 50 μm cloth and celite bed within 3 hours. After recharging the filtrate phase separated to remove the lower aqueous phase (1500 L) organic phase was retained as waste. The aqueous phase was charged to a 1380 L glass lined reactor and set for distillation at maximum Ti=61.3° C. and vac 180 mbar removing 1800 L distillate. Water charged and then heated to Ti=65.3° C. within 90 minutes. pH adjusted with 6.2% hydrochloric acid to pH 5.5 within 180 minutes. Cooled to Ti<20° C. within 180 minutes then filtered on a stainless steel nutsche filter, equipped with 50 μm cloth, within 10 hours. Pull dried and displacement washed to isolate damp off white solid 588 kg.
(77) Result:
(78) 588 kg uncorrected (LOD Content 30% w/w=176.4 Kg, Yield (Corr): 48.1%) HPLC Purity: 81.26% (area %)
(79) HPLC Chiral Purity: 95.03% (area % S Isomer)
(80) First Recrystallisation
(81) A dry 2800 L glass lined reactor was charged at Ti=20° C. with 4-Amino-6-hydroxy-2-[(15)-1-(phenylethyl)thio]pyrimidine and methanol, heated to Ti=55° C. within 120 minutes and kept for 1 hours. By method of in-line GAFF filter the solution was transferred at Ti=55° C. to a 4500 L glass lined vessel, on completion washed lines through with methanol. Heat applied to Ti=65° C. (reflux) and kept for 1 hour, charged water within 3 hours maintaining Ti>60° C. Agitation reduced and cooled slowly to Ti=22.5° C. within 6 hours. Filtered on stainless steel nutsche filter equipped with 50 μm cloth within 12 hours, pull dried and displacement washed pull dried to isolate 302 kg of off white solid.
(82) Result:
(83) 302 kg uncorrected
(84) HPLC Purity: 95.11% (area %)
(85) HPLC Chiral Purity: 97.09% (area % R Isomer) (area % S Isomer)
(86) Second Recrystallisation
(87) A dry 4500 L glass lined reactor was charged at Ti=20° C. with 4-Amino-6-hydroxy-2-[(1S)-1-(phenylethyl)thio]pyrimidine and methanol, heated to Ti=65° C. (reflux) within 50 minutes and kept for 30 minutes, charged water within 3 hours maintaining Ti>60° C. Agitation reduced and cooled slowly to Ti=23.1° C. within 6 hours. Filtered on stainless steel nutsche filter equipped with 50 μm cloth within 12 hours, pull dried and displacement washed, pull dried to isolate 142 kg of off white solid. Dried in Cone Vac Dryer at maximum Ti=60° C. and 20 mbar.
(88) Result:
(89) 106 kg uncorrected (LOD Content 99.1% w/w=105.1 Kg, Yield (Corr): 61.1%) HPLC Purity: 94.07% (area %) HPLC Chiral Purity: 99.04% (area % S Isomer)
(90) Summary
(91) Two synthetic steps and two recrystallisations were necessary to achieve a chiral purity of >99%.
(92) The overall yield of the process was 29.3% (including the recrystallisation steps).