Article pubs.acs.org/OPRD
Evaluation of Novel Synthetic Methods for the Preparation of the Sodium Channel Inhibitor, GW273225X Matthew D. Walker,* F. David Albinson, Hugh F. Clark, Stacy Clark, Nicholas P. Henley, Richard A. J. Horan, Chris W. Jones, Charles E. Wade, and Richard A. Ward Product Development, GlaxoSmithKline Pharmaceuticals, Medicines Research Centre, Gunnels Wood Road, Stevenage, SG1 2NY, U.K. S Supporting Information *
ABSTRACT: The evaluation of efficient synthetic methods for the preparation of (R)-2,4-diamino-5-(2,3-dichlorophenyl)-6fluoromethylpyrimidine, GW273225X (1), is described. The initial synthesis using ethylfluoroacetate was evaluated against three alternative routes using either nucleophilic fluorination, electrophilic fluorination, or sodium fluoroacetate.
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INTRODUCTION GW273225X 1 (Figure 1) was initially candidate-selected in 1995 for neuropathic pain, but development was stopped in
ether 5 was treated with guanidine hydrochloride and NaOMe in methanol to give the racemic 2,4-diaminopyrimidine 6 in 56% overall yield from nitrile 3. Resolution of the racemate 6 was then effected by forming the DBTA salt.3 At this point a recrystallisation was required in order to obtain the salt with the required de, giving the DBTA salt 7 in 35% yield from the racemate 6. The DBTA salt 7 was free-based by treatment with Et3N before recrystallisation of intermediate grade material to give the desired product GW273225X 1 in 83% yield and >99% ee from the DBTA salt 7.4 The high toxicity of the materials being used in this synthesis required the adoption of stringent safety control measures, causing the cycle time of this process to become protracted. We therefore chose to investigate a number of alternative routes to the racemate of GW273225X 1 that avoided or minimised the use of ethyl fluoroacetate and ethyl iodide. Development of Alternative Routes to GW273225X 1Use of Nucleophilic Fluorination. Previous investigations, which focused on the deoxyfluorination of alcohol 11, had identified (diethylamino)sulfur trifluoride (DAST) as the only successful reagent for completing this transformation (see Scheme 2).1a,5 Synthesis of the alcohol 11 was carried out by Claisen condensation of nitrile 3 with ethyl diethoxyacetate, followed by O-alkylation and guanidination to give acetal 9. The acetal 9 was hydrolysed and reduced with sodium borohydride to give the alcohol 11 in 43% yield from nitrile 3. We then focused on optimisation of the direct deoxyfluorination of alcohol 11 using DAST.6 A limited range of compatible solvents were screened with no success. A screen of reaction conditions, including concentration, temperature, and DAST stoichiometry, was carried out but failed to improve on the previously identified reaction conditions. Alcohol 11 was then deoxyfluorinated using 5 equiv of DAST in DCM, which gave the racemate 6 in 87% yield. The requirement for large excesses of potentially explosive DAST and cryogenic reaction temperatures meant work in this area was terminated.
Figure 1. GW273225X 1 and lamotrigine (Lamictal) 2.
1997 due to a lack of efficacy. The program was restarted in 2005 as a follow-up to lamotrigine 2 (Lamictal) after evaluation for bipolar disorder and epilepsy.1 Initial toxicology and clinical studies were supplied via a route that started from a Claisen condensation of 2,3dichlorophenylacetonitrile 3 with highly toxic ethylfluoroacetate.2 The material was provided as a single atropisomer by usage of a classical resolution procedure. Before preparing further supplies of material, we were keen to assess the viability of alternative routes. We report here how three new routes to GW273225X were identified and their suitability for large-scale manufacture evaluated.
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RESULTS AND DISCUSSION Initial Supply Route to GW273225X 1. The synthesis of GW273225X 1 (Scheme 1) was carried out by first preparing the racemic 2,4-diaminopyrimidine 6 in three telescoped stages followed by resolution using dibenzoyl-L-tartaric acid hydrate (DBTA·H2O). Claisen condensation of nitrile 3 with 1.5 equiv of ethylfluoroacetate promoted by NaOMe in methanol gave enol 4 after acidification of the reaction mixture with aqueous HCl. Care was required at this point due to the instability of the enol product towards the retro-Claisen reaction. The wet cake obtained from the isolation of 4 was alkylated with EtI and K2CO3 in DMF after azeotropic drying, and the resultant enol © XXXX American Chemical Society
Received: July 1, 2013
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Scheme 1. Route A to GW273225X 1 via Ethylfluoroacetate
Scheme 2. Synthesis of Racemic Diaminopyrimidine 6 via Deoxyfluorination
Scheme 3. Synthesis of Racemic Diaminopyrimidine 6 via Nucleophilic Fluorination
water to control the precipitation of the product and cleanly afford the fluoride 6 in 58% yield from the alcohol 11. Development of Alternative Routes to GW273225X 1Use of Electrophilic Fluorination. Electrophilic fluorination was an attractive option due to the simpler synthesis of the required substrates and the ready access to a range of easily handled electrophilic fluorinating agents.9 It was felt that the analogous des-fluoro enol ether 14 would be the most viable substrate for this approach due to concerns about reagent compatibility with other substrates, such as the analogous desfluoro 2,4-diaminopyrimidines. Initially an adaptation of the existing route was used with methyl acetate replacing the toxic ethyl fluoroacetate.10 The initial Claisen reaction was significantly slower than with ethyl fluoroacetate even with higher stoichiometries of both base and methyl acetate. The enol 13 was isolated as an oil and alkylated
An alternative stepwise strategy was subsequently investigated, whereby alcohol 11 would be converted into an intermediate mesylate 12 and then transformed into the desired fluoride 6.7 Although the mesylate 12 could be formed in situ, we were initially unable to transform the mesylate 12 into the fluoride 6 using CsF. Pleasingly, the use of the ionic liquid [bmim][BF4] as a solvent cleanly afforded the required fluoride 6, and subsequent factor screening identified that the ionic liquid could be employed as a cosolvent.8 We found that only 1.25 equiv of the ionic liquid and 1.25 equiv of CsF with respect to the alcohol 11 were required to produce the fluoride 6 in aqueous acetonitrile (Scheme 3). Unfortunately, owing to the low solubility of the fluoride 6 in many organic solvents, isolation of the product from the ionic liquid proved difficult. This was circumvented by the addition of DMSO to the reaction mixture, followed by slow addition of B
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Development of Alternative Routes to GW273225X 1Use of Sodium Fluoroacetate. We decided to investigate the use of alternative fluoroacetate analogues in order to minimise the fluoroacetate stiochiometry required in Stage 1 and to simplify and reduce both the process cycle time and the waste streams generated. It was found that sodium fluoroacetate (SFA) was the only readily commercially available fluoroacetate synthon, and it was anticipated that by use of an appropriate activating agent the condensation reaction would only require a stoichiometric amount of SFA.13,14 Screening of activating agents demonstrated 1,1′-carbonyldiimidazole (CDI) to be a viable reagent for this activation, and addition of 1.2 equiv of CDI to a slurry of nitrile 3 and 1 equiv of SFA in DMF at 80 °C promoted the formation of the sodium enolate 15 with good conversion. A number of solvents were screened in an attempt to replace DMF, but due to the low solubility of CDI, DMF was found to be optimal in keeping the process volume efficient. A method for conversion of the sodium enolate 15 to the 2,4-diaminopyrimidine 6 was then required that avoided the highly inefficient isolation of the enol 4. Direct O-alkylation of the reaction mixture generated from the CDI mediated Claisen condensation failed to go to completion using the original conditions, and the alkylation was found to require 6 equiv of ethyl iodide due to competitive alkylation of imidazole generated from the CDI reaction.15 Alternative methods for forming the enol ether 5 were investigated, using further various activating agents, followed by quenching with ethanol, but only the starting enol 4 was observed in any reaction. We did find that treatment of the sodium enolate 15 with thionyl chloride cleanly gave a new product which was eventually identified as the imidazolide 16 rather than the analogous vinyl chloride as expected. Due to the potential formation of toxic dimethylcarbamoyl chloride (DMCC) from DMF and thionyl chloride, we elected to screen a number of alternative activating agents. After screening, it was established that the use of propylphosphonic anhydride (T3P) also readily generated the same imidazolide 16 with good conversion. Optimisation showed that the addition of 1.1 equiv of T3P (50% w/w in ethyl acetate) to a solution of the sodium enolate 15 at 30 °C initially generated the corresponding activated phosphonic ester and only increasing the temperature to 80 °C promoted complete conversion to the imidazolide 16. Following work up with aqueous potassium carbonate and a solvent swap into methanol, the crude imidazolide 16 was condensed with guanidine hydrochloride using sodium methoxide in methanol to give the desired 2,4-diaminopyrimidine 6. This efficient one-pot telescoped process was carried out using these reactions to yield 2,4-diaminopyrimidine 6 in 46% overall yield over the three stages (Scheme 5). Evaluation of Alternative Routes to GW273225X 1. The evaluation of the synthetic routes towards GW273225X 1 was carried out using decision analysis methods based on a weighting of the desired attributes for the synthesis and an evaluation of each route against these attributes (see Table 1).16 The evaluation shows clearly that the SFA route performs the best in this analysis, primarily due to the efficiency of the onepot telescoped process. The cycle time for the SFA process was anticipated to be much lower than the current process, and the application of the novel Claisen condensation reaction significantly reduced the toxicity of the process by cutting the amount of fluoroacetate used to 1 equiv. The development of a new activation strategy, using T3P as a significantly safer
under the ethyl iodide conditions used previously to give the enol ether 14 in order to investigate the fluorination. The enol ether 14 was extracted into toluene, washed with aqueous NaCl, and distilled in order to remove the DMF and ensure azeotropic drying of the product solution ready for use in the fluorination. The direct fluorination of the enol ether 14 was initially investigated by treatment with NaHMDS at −20 °C followed by the addition of fluorinating agent N-fluorobenzenesulphonimide (NFSI), which was shown to give the desired fluorinated enol ether 5.11 Optimisation of the reaction conditions was carried out between −20 and 0 °C and included a range of bases (strong and weak, organic and inorganic), solvents (ethers, toluene, and heptane), reagent equivalents, concentrations, and NFSI addition rates. Only the strong bases (LDA and MHMDS where M = Li, Na, K) gave any significant amount of product, and the use of LiHMDS in THF at lower temperatures was found to be optimal (although 2-MeTHF and toluene also gave good results). The other critical factor was found to be the rate of addition of the NFSI which needed to be as fast as possible, presumably in order to prevent equilibration of the anionic species in the reaction (hence leading to under- and overfluorinated products). However, it was also found that the reaction of the anion of the enol ether 14 with NFSI was very exothermic, preventing us from carrying out the NFSI addition rapidly. This problem was overcome by a reverse addition protocol, whereby a solution of the anion was added to a solution of NFSI. This allowed the exotherm to be controlled by the rate of addition and also reduced the potential for anion exchange, thereby reducing the levels of under- and overfluorinated impurities. A basic workup of this reaction was also desired to avoid the potential of generating hydrofluoric acid, and after a study of different workup conditions, it was found that quenching the THF/toluene reaction mixture with dilute aqueous sodium bicarbonate allowed the complete removal of the NFSI derived byproducts after two washes with minimal loss of the desired enol ether 5 to the aqueous phases. Following removal of THF by distillation, the toluene solution of enol ether 5 was reacted with guanidine hydrochloride under the reaction conditions used in the original route to give 2,4-diaminopyrimidine 6 in 40% overall yield from the nitrile 3 (Scheme 4).12 Scheme 4. Synthesis of Racemic Diaminopyrimidine 6 via Electrophilic Fluorination
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give a white crystalline solid (104.1 g). This solid (92.0 g) was slurried in a mixture of propan-1-ol (538 mL) and water (290 mL) and heated to 80 ± 3 °C for 30 min to give a clear solution. The resulting solution was filtered to a clean vessel followed by a mixture of propan-1-ol (59.8 mL) and water (32.2 mL) at 80 ± 3 °C and cooled to 71 ± 3 °C. The mixture was seeded with (R)-2,4-diamino-5-(2,3-dichlorophenyl)-6fluoromethylpyrimidine (1) (92 mg) in propan-1-ol (1.84 mL) and the mixture aged for 2 h at 71 ± 3 °C. The slurry was cooled to 0 ± 3 °C over 4.5 h. Water (1077 mL) was added over 8 h, stirred for 1 h, and filtered. The cake was washed with a mixture of propan-1-ol (37.5 mL) and water (87.5 mL) and with water (2 × 125 mL) and pulled dry. The solid was dried under vacuum at 70 ± 5 °C to give a white solid (81.9 g, 83% overall yield): [α]20 D −56.75 (c = 0.53, EtOH). mp 215−216 °C. 1 H NMR (400 MHz, d6-DMSO) δ 7.63 (dd, J = 8.1, 1.5 Hz, 1H), 7.39 (t, J = 7.8 Hz, 1H), 7.24 (dd, J = 7.8, 1.5 Hz, 1H), 6.18 (br s, 2H), 6.03 (br s, 2H), 4.82 (dd, J = 22.5, 11.0 Hz, 2H), 4.70 (dd, J = 22.5, 11.0 Hz, 2H). 13C NMR (100 MHz, d6DMSO) δ 162.7 (C), 162.0 (C), 158.1 (d, J = 15.0 Hz, C), 135.7 (C), 132.7 (C), 132.1 (C), 131.6 (CH), 130.2 (CH), 128.4 (CH), 104.7 (d, J = 3.1 Hz, C), 82.5 (d, J = 167.5 Hz, CH2). 19F NMR (376 MHz, d6-DMSO) δ −216.7 (t, J = 47.8 Hz). MS (ES+): m/z 287 [M + H]+. 2,4-Diamino-5-(2,3-dichlorophenyl)-6-fluoromethylpyrimidine (6) from 2,3-Dichlorophenylacetonitrile (3)Method A (Ethylfluoroacetate). 2,3-Dichlorophenylacetonitrile (3) (100 g, 538 mmol) was suspended in methanol (200 mL) and cooled to 10 ± 5 °C. 30% (w/w) Sodium methoxide in methanol solution (400 mL, 2.16 mol) was added followed by methanol (20 mL), maintaining the temperature of the reaction mixture below 30 °C. The temperature was adjusted to 20 ± 5 °C. Ethylfluoroacetate (CAUTION: highly toxic) (78 mL, 807 mmol) was added followed by methanol (35 mL). The reaction mixture was stirred at 20 ± 5 °C for 18 h. The reaction mixture was cooled to 5 ± 5 °C and added into a mixture of 32% (w/w) aqueous hydrochloric acid (320 mL) and water (1150 mL) over 40 min, followed by methanol (45 mL), maintaining the temperature below 20 °C. The reaction mixture was warmed to 20 ± 5 °C over 60 min. The resultant slurry was filtered and the cake washed with a mixture of water (330 mL), methanol (150 mL), and 32% (w/w) aqueous hydrochloric acid (22.5 mL) before pulling dry. The cake was dissolved in ethyl acetate (800 mL), the solution transferred to the reaction vessel followed by ethyl acetate (50 mL), and the organic solution was then washed with a solution of 20% (w/w) aqueous sodium chloride (45 mL) at 20 ± 5 °C. The mixture was then washed with a solution of 20% (w/w) aqueous sodium chloride (90 mL) at 20
Scheme 5. Synthesis of Racemic Diaminopyrimidine 6 via Claisen Condensation with SFA
alternative to ethyl iodide, also reduced the number of waste streams generated from 8 to 3 by telescoping the activation and guanidine condensation. Consequently, in developing a one-pot process we have eliminated the transfer of highly toxic reaction mixtures and have therefore made the process operationally safer.17
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SUMMARY In conclusion, three new routes have been developed suitable for the synthesis of GW273225X 1 in up to 15% overall yield, including an unusual CDI and T3P mediated heterocycle synthesis.18 These new routes were evaluated against the current route using decision analysis methods to provide a clear candidate for further process development.
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EXPERIMENTAL SECTION General. (R)-2,4-Diamino-5-(2,3-dichlorophenyl)-6-fluoromethylpyrimidine (1) from (R)-2,4-Diamino-5-(2,3-dichlorophenyl)-6-fluoromethylpyrimidine·DBTA Salt (7). (R)-2,4Diamino-5-(2,3-dichlorophenyl)-6-fluoromethylpyrimidine· DBTA salt (7) (250 g, 387 mmol) was dissolved in a mixture of DMSO (675 mL) and water (75 mL) at 20 ± 5 °C. Triethylamine (113 mL, 811 mmol) was added and the mixture stirred at 20 ± 5 °C for 15 min. The solution was seeded with (R)-2,4-diamino-5-(2,3-dichlorophenyl)-6-fluoromethylpyrimidine (1) (200 mg) and aged for 90 min. Water (875 mL) was added over 75 min; the resultant slurry was aged at 20 ± 5 °C for 60 min and filtered. The cake was washed with water (2 × 375 mL), pulled dry, and dried under vacuum at 50 ± 5 °C to Table 1. Evaluation of Routes to Diaminopyrimidine 6 criteria
weighta
EFA routeb
F− routeb
F+ routeb
SFA routeb
steps health and safety purity yield environmental throughput totalc
2 4 5 3 4 3
5 1 5 4 1 1 58
2 4 3 1 3 4 62
4 3 4 3 3 4 73
5 1 5 3 4 5 79
a Scores for each weighting were given from 1 = least important to 5 = most important. bScores for each category were given from 1 = meets the criteria least successfully to 5 = meets the criteria most successfully. cThe total score was given by the sum of the products of the weighting and the scoring for each category.
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5 ± 5 °C followed by DMF (50 mL), maintaining the temperature below 20 °C. The reaction mixture was stirred at 15 ± 5 °C for 60 min, and ethyl iodide (86 mL, 1.08 mol) was added in a single portion followed by DMF (20 mL). The reaction mixture was heated to 65 ± 5 °C over 1 h and stirred at 65 ± 5 °C for 4 h. The mixture was cooled to 25 ± 5 °C; toluene was added (600 mL) and the mixture washed with water (800 mL) at 20 ± 5 °C. The organic phase was washed with a solution of 5% (w/w) aqueous sodium chloride (350 mL), and the organic solution was distilled under vacuum at 125 ± 50 mbar with the jacket set at 65 °C down to 130 mL and cooled to 20 ± 5 °C. The organic solution was distilled down to 154 mL in volume, under vacuum at 125 ± 50 mbar with the jacket set at 60 ± 5 °C and cooled to 20 ± 5 °C. To a stirred mixture of 72 mL of this solution and toluene (125 mL) at −25 ± 5 °C was added a 1 M in THF LiHMDS solution (216 mL, 216 mmol), maintaining the temperature below −15 °C. This solution was added over 2 h to a solution of NFSI (68 g, 216 mmol) in THF (250 mL) at 0 ± 5 °C via cannula. The reaction mixture was stirred at 0 ± 5 °C for a further 1 h and quenched by the addition of 8% (w/w) aqueous sodium bicarbonate (100 mL), followed by water (150 mL). The reaction mixture was warmed to 20 ± 5 °C and allowed to separate. The organic phase was washed with a mixture of 8% (w/w) aqueous sodium bicarbonate (100 mL) and water (150 mL). The organic phase was distilled down to 100 mL in volume, under vacuum at 100 ± 50 mbar with the jacket set at 45 °C. Toluene (100 mL) was added, and the reaction mixture was distilled down to 70 mL in volume, under vacuum at 100 ± 50 mbar with the jacket set at 65 °C. The resulting mixture was added to a stirred mixture of guanidine hydrochloride (12.2 g, 128 mmol) and 30% (w/w) sodium methoxide in methanol solution (24 mL, 126 mmol) in methanol (30 mL), followed by methanol (20 mL) maintaining the temperature below 25 °C. The reaction mixture was heated to 30 ± 5 °C over 30 min, stirred at 30 ± 5 °C for 3 h, and cooled to 20 ± 5 °C over 30 min. The reaction mixture was stirred at 20 ± 5 °C for 40 min, and the resultant slurry was filtered. The cake was washed with methanol (3 × 20 mL), pulled dry, and dried under vacuum at 50 ± 5 °C to give a cream coloured crystalline solid (13.07 g, 40% yield). 2,4-Diamino-5-(2,3-dichlorophenyl)-6-fluoromethylpyrimidine (6) from 2,3-Dichlorophenylacetonitrile (3)Method C (Sodium Fluoroacetate). 2,3-Dichlorophenylacetonitrile (3) (100 g, 538 mmol) and sodium fluoroacetate (CAUTION: highly toxic) (54 g, 538 mmol) were suspended in ethyl acetate (200 mL) and the temperature adjusted to 75 ± 5 °C. The slurry was aged for 1 h, and a solution of 1,1′-carbonyldiimidazole (105 g, 648 mmol) in dimethyl formamide (400 mL) was added over 2 h, followed by dimethyl formamide (20 mL). The reaction mixture was stirred at 75 ± 5 °C for 30 min. 50% (w/w) Propanephosphonic cyclic anhydride in ethyl acetate (352 mL, 591 mmol) was added and the mixture aged for 3 h at 75 ± 5 °C. The mixture was cooled to 20 ± 5 °C; toluene (400 mL) was added and then washed with 18.8% (w/ w) aqueous potassium carbonate solution (400 g). The organic solution was then washed with 5% (w/w) aqueous LiCl solution (400 g) at 20 ± 5 °C. Methanol (400 mL) was added, and the organic phase was distilled down to 200 mL in volume, under vacuum at 120 ± 50 mbar with the jacket set at 65 °C. The reaction mixture was cooled to 20 ± 5 °C, and then guanidine hydrochloride (51.4 g, 538 mmol) and methanol (200 mL) were added. 30% (w/w) Sodium methoxide in
± 5 °C and distilled down to 380 mL in volume, under vacuum at 200 ± 50 mbar at with the jacket set at 55 °C. DMF (130 mL) was added and the organic solution distilled down to 250 mL in volume, under vacuum at 200 ± 50 mbar with the jacket set at 55 °C. The reaction mixture was cooled to 5 ± 5 °C and added over 20 min to a suspension of potassium carbonate (93.3 g, 675 mmol) in DMF (300 mL) at 5 ± 5 °C followed by DMF (50 mL), maintaining the temperature below 20 °C. The reaction mixture was stirred at 15 ± 5 °C for 60 min, and ethyl iodide (86 mL, 1.08 mol) was added in a single portion followed by DMF (20 mL). The reaction mixture was heated to 65 ± 5 °C over 1 h and stirred at 65 ± 5 °C for 4 h. The mixture was cooled to 25 ± 5 °C, toluene was added (600 mL), and the mixture was washed with water (800 mL) at 20 ± 5 °C. The organic phase was washed with a solution of 5% (w/w) aqueous sodium chloride (350 mL). The organic solution was distilled under vacuum at 125 ± 50 mbar with the jacket set at 65 °C down to 130 mL and cooled to 20 ± 5 °C. The resultant mixture was added over 40 min to a mixture of guanidine hydrochloride (56.4 g, 590 mmol) and 30% (w/w) sodium methoxide in methanol (110 mL, 594 mmol) in methanol (155 mL), followed by methanol (35 mL) maintaining the temperature below 25 °C. The reaction mixture was heated to 30 ± 5 °C over 30 min, stirred at 30 ± 5 °C for 3 h, and cooled to 20 ± 5 °C over 30 min. A mixture of methanol (300 mL) and water (300 mL) was added over 30 min, maintaining the temperature of the reaction mixture at 20 ± 5 °C. The reaction mixture was stirred at 20 ± 5 °C for 40 min, and the resultant slurry was filtered. The cake was washed with methanol (4 × 200 mL), pulled dry, and dried under vacuum at 50 ± 5 °C to give a cream coloured crystalline solid (86.6 g, 56.1% yield). 2,4-Diamino-5-(2,3-dichlorophenyl)-6-fluoromethylpyrimidine (6) from 2,3-Dichlorophenylacetonitrile (3)Method B (Electrophilic Fluorination). 2,3-Dichlorophenylacetonitrile (3) (100 g, 538 mmol) was suspended in methanol (200 mL) and cooled to 10 ± 5 °C. 30% (w/w) Sodium methoxide solution (410 mL, 2.15 mol) was added followed by methanol (20 mL), maintaining the temperature of the reaction mixture below 30 °C. The temperature was adjusted to 20 ± 5 °C. Methyl acetate (65 mL, 818 mmol) was added followed by methanol (35 mL). The reaction mixture was stirred at 20 ± 5 °C for 18 h. Methyl acetate (22 mL, 278 mmol) was added, and the reaction mixture was stirred at 20 ± 5 °C for 24 h. Methyl acetate (44 mL, 554 mmol) was added, and the reaction mixture was stirred at 20 ± 5 °C for a further 24 h. The reaction mixture was cooled to 5 ± 5 °C and added into a mixture of 32% (w/w) aqueous hydrochloric acid (274 mL) and water (1200 mL) over 60 min. The reaction mixture was extracted with ethyl acetate (800 mL) and then ethyl acetate (400 mL) at 20 ± 5 °C. The combined organic extracts were washed with 20% (w/w) aqueous sodium chloride (50 mL), followed by 20% (w/w) aqueous sodium chloride (100 mL) at 20 ± 5 °C. The organic solution was distilled down to 150 mL in volume, under vacuum at 200 ± 50 mbar with the jacket set at 40 ± 5 °C. The organic solution was diluted with ethyl acetate (500 mL) and distilled down to 350 mL in volume, under vacuum at 200 ± 50 mbar with the jacket set at 40 ± 5 °C. DMF (130 mL) was added and the organic solution distilled down to 300 mL in volume, under vacuum at 200 ± 50 mbar with the jacket set at 55 °C. The resultant mixture was cooled to 5 ± 5 °C and added over 20 min to a suspension of potassium carbonate (93.3 g, 675 mmol) in DMF (300 mL) at E
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71.7 (CH). 19F NMR (376 MHz, d6-DMSO) δ −217.8 (t, J = 47.8 Hz). MS (ES+): m/z 287 [M + H]+.
methanol (102 mL, 551 mmol) was charged to the reaction maintaining the temperature at 20 ± 5 °C, followed by methanol (20 mL). The reaction mixture was warmed to 45 ± 5 °C and stirred for 3 h. Water (400 mL) was added; the mixture was cooled to 20 ± 5 °C and stirred for 30 min. The resultant slurry was filtered, and the cake was washed with a mixture of water (100 mL) and methanol (100 mL). The cake was washed with methanol (2 × 200 mL), and the solid was dried under vacuum at 50 ± 5 °C to give a cream coloured crystalline solid (71.0 g, 46% yield): mp 224−226 °C. 2,4-Diamino-5-(2,3-dichlorophenyl)-6-fluoromethylpyrimidine (6) from 2,4-Diamino-5-(2,3-dichlorophenyl)-6-hydroxymethylpyrimidine (11).1 To a stirred suspension of 2,4diamino-5-(2,3-dichlorophenyl)-6-hydroxymethylpyrimidine (11) (2.0 g, 7.01 mmol) in dichloromethane (20 mL) was added triethylamine (1.37 mL, 8.48 mmol) and DMAP (5 mg, 0.04 mmol) followed by methanesulphonic anhydride (1.47 g, 8.42 mmol), and the reaction mixture was stirred at 20 ± 5 °C for 1 h. Further triethylamine (0.49 mL, 2.83 mmol) and methanesulphonic anhydride (0.61 g, 3.49 mmol) were added, and the reaction was stirred at 20 ± 5 °C for a further 15 min. The reaction mixture was filtered and washed with DCM (2 × 4 mL). The crude solid was suspended in a mixture of acetonitrile (3 mL) and water (0.6 mL), and then [bmim][BF4] (1.65 mL, 8.84 mmol) and CsF (1.33 g, 8.84 mmol) were added. The reaction was heated to 90 ± 5 °C for 6 h and cooled to 20 ± 5 °C. The reaction mixture was diluted with DMSO (15 mL) and water (7 mL) before water (20 mL) was added over 10 h. The resultant solid was filtered and washed with water (2 × 4 mL) to give a white solid (0.49 g, 24% yield). (R)-2,4-Diamino-5-(2,3-dichlorophenyl)-6-fluoromethylpyrimidine·DBTA Salt (7) from 2,4-Diamino-5-(2,3-dichlorophenyl)-6-fluoromethylpyrimidine (6). 2,4-Diamino-5-(2,3dichlorophenyl)-6-fluoromethylpyrimidine (6) (80 g, 279 mmol) was added to a solution of dibenzoyl-L-tartaric acid hydrate (105 g, 279 mmol) in a mixture of water (125 mL) and industrial methylated spirits (IMS) (590 mL) at 20 ± 5 °C followed by IMS (160 mL). The resultant suspension was heated to 65 ± 5 °C for 16 h, cooled to 20 ± 5 °C over 2 h, and aged for 3 h. The solid was filtered and the cake washed with a mixture of IMS (272 mL) and water (48 mL), with IMS (2 × 320 mL), and pulled dry. The solid was dried under vacuum at 45 ± 5 °C to give a white crystalline solid (84.3 g). This solid (80.0 g) was slurried in a mixture of DMSO (80 mL) and IMS (136 mL) and heated to 65 ± 5 °C to give a clear solution that was cooled to 55 ± 5 °C and seeded with (R)-2,4-diamino-5(2,3-dichlorophenyl)-6-fluoromethylpyrimidine·DBTA salt (7) (80 mg) in IMS (0.5 mL). The mixture was aged for 15 min ,and IMS (584 mL) was added over 1 h. The slurry was cooled to 20 ± 5 °C over 70 min, aged for 2 h, and filtered. The cake was washed with a mixture of DMSO (16 mL) and IMS (144 mL), with IMS (2 × 160 mL), and pulled dry. The solid was dried under vacuum at 50 ± 5 °C to give a white solid (59.6 g, 34.9% yield): 1H NMR (400 MHz, d6-DMSO) δ 8.01 (m, 8H), 7.71 (m, 4H), 7.67 (dd, J = 8.1, 1.5 Hz, 1H), 7.41 (t, J = 7.8 Hz, 1H), 7.25 (dd, J = 7.6, 1.5 Hz, 1H), 6.76 (br s, 2H), 6.52 (br s, 2H), 5.83 (s, 2H), 4.87 (dd, J = 15.9, 11.3 Hz, 1H), 4.75 (dd, J = 15.9, 11.3 Hz, 1H). 13C NMR (100 MHz, d6-DMSO) δ 167.5 (C), 164.7 (C), 162.2 (C), 160.6 (C), 154.8 (d, J = 15.3 Hz, C), 134.2 (CH), 133.8 (CH), 132.6 (C), 132.2 (C), 131.5 (CH), 130.5 (CH), 129.3 (CH), 128.9 (CH), 128.7 (C), 128.5 (CH), 105.2 (d, J = 3.5 Hz, C), 81.9 (d, J = 167.9 Hz, CH2),
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ASSOCIATED CONTENT
S Supporting Information *
General methods description and spectral data for (R)-2,4diamino-5-(2,3-dichlorophenyl)-6-fluoromethylpyrimidine (1), 2,4-diamino-5-(2,3-dichlorophenyl)-6-fluoromethylpyrimidine (6), and (R)-2,4-diamino-5-(2,3-dichlorophenyl)-6-fluoromethylpyrimidine·DBTA salt (7). This material is available free of charge via the Internet at http://pubs.acs.org.
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AUTHOR INFORMATION
Corresponding Author
*Telephone: 01438 551179. E-mail: Matthew.D.Walker@GSK. com. Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS We thank our R&D Product Development colleagues Keith Allworth and David Stevens from Synthetic Chemistry, Marcello Murru from Process Design, and Julien Patoor from Analytical Sciences. We also thank our colleagues Paul Evans and Jamie Russell from Investigational Material Supply.
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REFERENCES
(1) (a) Nobbs, M. S.; Rodgers, S. J. Preparation of (R)-2,4-diamino-5(2,3-dichlorophenyl)-6-fluoromethylpyrimidine as a drug. World Patent WO 9709317 A2, 1997. (b) Miller, A. A.; Nobbs, M. S.; Hyde, R. M.; Leach, M. J. Preparation and formulation of phenylpyrimidines for treating central nervous system disorders. European Patent EP 372934, 1996. (c) Alvaro, G.; Large, C. Pharmaceutical compositions comprising 3,5-diamino-6-(2,3-dichlorophenyl)-1,2,4-triazine or R-(−)-2,4-diamino5-(2,3-dichlorophenyl)-6-(fluoromethyl)pyrimidine and an NK1 antagonist. World Patent WO 2008090117 A1, 2008. (2) The UK HSE has assigned a SLOD DTL (Specified Likelihood of Death Dangerous Toxic Load) for ethyl fluoroacetate as 1840 ppm· min. For example, it is estimated that, for exposure of a population to 80 ppm of ethyl fluoroacetate for 23 min (1840 ppm·min), 50% of this population would be killed [Assessment of the Dangerous Toxic Load (DTL) for Specified Level of Toxicity (SLOT) and Significant Likelihood of Death (SLOD)]. http://www.hse.gov.uk/chemicals/ haztox.html (accessed April 19, 2013). (3) Other chiral acids were evaluated in the salt formation, but only DBTA was shown to give any diastereoselectivity in the crystallisation of the respective salt. (4) The recrystallisation of enatiomerically enriched GW273225X 1 was performed under carefully temperature controlled conditions in order to avoid excessive epimerisation of the chiral atropisomeric axis. A graph of the effect of temperature and time on the enantiomeric excess of the product was generated and used to define the processing conditions. (5) Šilhár, P.; Pohl, R.; Votruba, I.; Hocek, M. Org. Biomol. Chem. 2005, 3001−3007. (6) Alternative deoxyfluorinating agents such as Deoxo-fluor (bis-(2methoxyethyl)aminosulphur trifluoride) were also investigated without success. (7) Treatment of the mesylate 12 with NaI in acetone cleanly afforded the corresponding iodide in good yield. Unfortunately, attempts to form the racemate 6 from the iodide by treatment with CsF failed to yield any of the desired product. (8) Kim, D. W.; Song, C. E.; Chi, D. Y. J. Org. Chem. 2003, 68, 4281−4285. (9) (a) Kirk, K. L. Org. Process Res. Dev. 2008, 12, 305−321. (b) Lal, G. S.; Pez, G. P.; Syvret, R. G. Chem. Rev. 1996, 96, 1737−1755. F
dx.doi.org/10.1021/op4001753 | Org. Process Res. Dev. XXXX, XXX, XXX−XXX
Organic Process Research & Development
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(10) Efforts were made to develop alternative routes to the enol ether 14; however use of more reactive acetate sources (acetic anhydride or acetyl chloride) did not give the desired enol 13 and instead gave the corresponding enol acetate, which did not undergo the desired reaction with guanidine hydrochloride. Attempts to synthesise the enol ether 14 directly using triethylorthoacetate under Brønsted or Lewis acidic conditions also failed to show any reaction. (11) Alternative commercial electrophilic fluorinating agents such as Selectfluor and N-fluoropyridinium tetrafluoroborate salts were also investigated without success. (12) The racemic 2,4-diaminopyrimidine 6 prepared by this new route shows excellent purity, containing only small amounts of the difluorinated analogue and none of the des-fluorinated analogue. Although the largest impurity going into the guanidination was residual enol ether 14, this reacted comparatively slowly in the guanidination reaction and was removed in the subsequent isolation. (13) Attempts at generation of fluoroacetic acid or fluoroacetyl chloride in organic solvent were unsuccessful due to either water solubility or instability of the desired compound. (14) Saunders, B. C.; Stacey, G. J. J. Chem. Soc. 1948, 1773−1779. (15) Initial studies showed it was possible to convert the isolated enol 4 into the enol ether 5 using triethyl orthopropionate and acetic acid. However, telescoping this methodology with the new CDI/sodium fluoroacetate synthesis of the enol 4 resulted in significant retroClaisen reaction, which was attributed to the presence of imidazole in the reaction mixture. (16) (a) Parker, J. S.; Moseley, J. D. Org. Process Res. Dev. 2008, 12, 1041−1043. (b) Moseley, J. D.; Brown, D.; Firkin, C. R.; Jenkin, S. L.; Patel, B.; Snape, E. W. Org. Process Res. Dev. 2008, 12, 1044−1059. (c) Parker, J. S.; Bower, J. F.; Murray, P. M.; Patel, B.; Talavera, P. Org. Process Res. Dev. 2008, 12, 1060−1077. (17) The hazard of sodium fluoroacetate is comparable to that of ethyl fluoroacetate, both being highly toxic. The level of risk from the two compounds was therefore judged to be largely affected by the ability to control exposure to the materials. A more detailed risk assessment of both processes would be required in order to judge this accurately. (18) The quoted yields for synthesis of GW273225X 1 do not include recycling of the unwanted enantiomer, which could be recovered by freebasing the unwanted diastereoisomer of the salt and thermally racemising (S)-2,4-diamino-5-(2,3-dichlorophenyl)-6-fluoromethylpyrimidine by heating as a slurry in toluene.
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dx.doi.org/10.1021/op4001753 | Org. Process Res. Dev. XXXX, XXX, XXX−XXX
