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Dehydration of an insoluble urea byproduct enables the condensation of DCC and malonic acid in flow. Alexander O'Brien, Eric M. Ricci, and Michel Journet Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.7b00375 • Publication Date (Web): 13 Feb 2018 Downloaded from http://pubs.acs.org on February 13, 2018
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Organic Process Research & Development
Dehydration of an insoluble urea byproduct enables the condensation of DCC and malonic acid in flow Alexander G. O’Brien,* Eric M. Ricci, Michel Journet GlaxoSmithKline, 709 Swedeland Road, King of Prussia, Pennsylvania 19406, United States. Supporting Information Placeholder ABSTRACT: A procedure for the preparation of N,N’dicyclohexylbarbituric acid from DCC and malonic acid is described. Addition of phosphorus oxychloride to the reaction mixture facilitates dehydration of the insoluble byproduct N,N’-dicyclohexyl urea, enabling operation in continuous flow. A development approach based on in situ monitoring of batch reactions was used, which supported screening and determination of reaction conditions at small scale prior to scaleup in flow. Additional mechanistic understanding and control of impurity formation are presented.
During a recent development program, we required a multi-kilogram quantity of N,N’-dicyclohexylbarbituric acid 2 for use as a synthetic intermediate, and therefore evaluated methods for its preparation. To minimize plant cycle time, we examined the suitability of known syntheses of N,N’1–3 dialkylbarbituric acids for operation in continuous flow. Common procedures based on condensation of malonic acid (Scheme 1) require handling of N,N’-dicyclohexyl urea (DCHU), a solid which we found to have very low solubility in a wide range of solvents vide infra, used either as starting 2 3 material (Route A) or a byproduct (Route B). Handling of solids in flow may be challenging: either a solvent must be found that gives a homogenous reaction mixture which is easily processed by existing equipment, or a reactor/pump 4 combination capable of handling slurries is required.
Scheme 1. Common dialkylbarbituric acids.
pathways
to
N,N’-
Aiming to select chemistry that would not require specialized equipment, and would run under homogeneous conditions, we determined solubility of DCHU and 2 in a range of solvents (Table 1).
Table 1. Solubility of DCHU and 2. Solvent
Solubility of DCHU (mg/mL)
Solubility (mg/mL)
iPrOH
7.3
2.8
MeOH
6.1
2.4
DMSO
2.3
28.7
THF
1.0
106.0
1,4-dioxane
0.5
49.0
acetone
0.4
19.4
MIBK
0.3
17.1
iPrOAc
0.3
21.4
MeCN
0.1
14.7
MTBE
0.1
7.0
H2O
0.0
0.2
PhMe
0.0
25.7
of
2
We elected not to use DCHU as starting material (Route A) based on its impractically low solubility. Instead, the high 5 6 solubility of both malonic acid and DCC in organic solvents led to the selection of Route B, using THF (in which 2 was most soluble) as solvent. However, a method was required for solubilization of the DCHU byproduct of this reaction. 7 Dialkyl ureas undergo dehydration to give salts 4, which 8 upon treatment with base give carbodiimides (Scheme 2a). We therefore proposed that the addition of a dehydrating agent to the DCC–malonic acid mixture would either lead to formation of a soluble salt 5 from DCHU generated during ring-closure, or ideally regenerate DCC to facilitate reaction using close to 1 equivalent of the reagent. We show herein how addition of POCl3 to the reaction mixture enabled the development of homogenous conditions that could be transferred to flow (Scheme 2b). Furthermore, we demonstrate how using in situ monitoring of small scale batch reactions
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Organic Process Research & Development can be used to gain mechanistic insight, optimize a reaction and rapidly transfer the process to continuous operation.
Scheme 2. (a) Dehydration of ureas to give carbodiimides; (b) proposed reaction of urea byproducts to enable handling in flow.
incomplete consumption of malonic acid, rather than any other unproductive pathway (Figure 1). Despite the observation that recycling of DCHU did not occur, using 2 equivalents of DCC gave complete consumption of malonic acid, giving 2 in 84% assay yield, and with the reaction still operating under homogenous conditions even at a concentration 10 close to the solubility limit of 2 (98 mg/mL, 0.34 M).
Figure 1. Consumption of malonic acid monitored by in situ IR.
Parallel screening in the presence of dehydration reagents 9 was performed in THF (Table 2) at approximately half the measured solubility of 2 (53 mg/mL 2, 0.18 M, assuming 100% conversion). Recycling of DCHU to DCC via 5 would be indicated if >50% conversion of malonic acid to 2 was observed when only 1 equivalent of DCC was used. Amongst the additives screened, POCl3 (entry 7) was the only reagent that gave a homogeneous reaction mixture, with 2 as the only species observed by HPLC, albeit in moderate assay yield, indicating that DCHU was not recycled to DCC as intended.
Table 2. Screening of dehydration reagents.
Entry
Equiv DCC
Additive
% a yield
1
2.0
none
78
2
1.0
none
21
3
1.0
P2O5
28
4
1.0
P2O5 (7% w/w in MeSO3H)
0
5
1.0
Ph3P
21
6
1.0
Ac2O
25
7
1.0
POCl3
49
a
assay
by HPLC
Peak height at 1744 cm-1 (malonic acid)
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
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0.7 0.6 0.5 0.4 0.3 0.2 0.1 0
1 equiv DCC 2 equiv DCC
0
50
100
Time (s)
Analysis of spectra obtained at single points along the reaction profile allowed identification of reactive intermediates, providing additional mechanistic details to aid optimization. Consumption of POCl3 and formation of a new species with -1 peaks at 1290 and 1664 cm occurred slower than the rate of DCC consumption. The frequencies of these vibrations suggested that the new species contained both P=O and C=N functional groups, and thus was likely a product of reaction between POCl3 and DCHU. Direct reaction of DCHU with POCl3 gave a species with identical spectroscopic properties. 31 1 P- and H-NMR confirmed the structure of the species as dichlorophosphate salt 5 (Scheme 3). Observation that DCC formed upon treatment of 5 with triethylamine (Figure 2) suggested that 2 could form with simultaneous regeneration of DCC from 5, thereby attaining high yield with reduced DCC loading if the reaction was run in the presence of base. However, despite extensive screening of bases and non-basic HCl scavengers (see Supporting Information), we were unable to find an additive that gave high yield with reduced DCC loading. No increase in product concentration was observed if base was added at the end of reaction and premixing of triethylamine and malonic acid prior to addition entirely suppressed formation of 2.
Scheme 3. Additional small-scale experiments using POCl3 were performed to understand the reaction and increase the yield prior to transfer to continuous flow. Preliminary studies following the reaction by HPLC showed [2] to plateau in less than 5 min. Furthermore, as neither malonic acid nor DCC were visible by HPLC, in situ IR was used for reaction monitoring. Comparing the reaction profiles using 1 and 2 equivalents of DCC highlighted that the low yield derived from
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Figure 2. Monitoring of the formation of 5 and its conversion to DCC on addition of triethylamine by IR.
Figure 3. Effect of malonic acid addition rate on formation of 7.
4.0 DCC
Species 5
3.0
1200
80 1.0 NEt3 added
NEt3 added
0.0 0
1000
2000
3000
4000
800
60 40
Time (s)
20
Scheme 4. Proposed mechanism
0
400 0 0
0.5
1
Peak area of 7 (mAu)
100
2.0
% yield 2
Peak Area
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
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1.5
Addition rate (mmol/s) % assay yield of 2
These data suggest a mechanism where malonic acid and DCC react to give 6, followed by reaction of a second equivalent of DCC to give 2 with concomitant formation of DCHU. DCHU then reacts with POCl3 to give 5, which remains at the end of the reaction (Scheme 4). While addition of base can facilitate conversion of 5 to DCC, it may prevent the protonation of DCC to give the active electrophile, and therefore slow the rate of formation of 6. Prior to scaleup in flow, we examined the impurity profile of the reaction/ In addition to 11 2 we observed formation of carbamoylguanidine 7, tentatively presumed to form by reaction of 5 with DCC–H2O or 12 DCHU (Scheme 5). Slow dosing of malonic acid to DCC– POCl3 in an automated batch reactor caused an increase in [7], indicating that its formation was favoured at low [malonic acid], rather than because of the initial exotherm (Figure 3). The observation that rapid addition of malonic acid at elevated temperature reduced the level of 7, further suggested the suitability of these conditions for transfer to flow, and indicated that the chemistry would be well-suited to a plugflow reactor setup.
Peak area of 7 (mAu)
The residence time in the flow reactor was determined using the previously collected IR time course data, which showed that that at least 3.5 min was required for both formation of 2 and 5 to occur, and thereby prevent clogging of the reactor with unreacted DCHU. Equimolar solutions of DCC and malonic acid–POCl3 were prepared and mixed in a 2:1 ratio, then passed through a heated loop. The concentrations of starting materials and target concentration of 2 were all set below their respective solubility limits. We found that, in agreement with IR data, a residence time of 3.6 min was sufficient to provide complete reaction without clogging, however priming the reactor with POCl3–THF prior to introduction of DCC and malonic acid was required to prevent clogging with DCHU during start-up. Slow accumulation of DCHU over time was observed when the reaction was run at 60 °C; increasing the temperature to 80 °C increased the robustness of the process, and the reactor was run without clogging for over 8 h. The product 2 was obtained in 85–87% yield, providing sufficient material to fund development of later steps in the route. Samples of 2 could be isolated by addition of the reaction output to iPrOH followed by recovery of the precipitate, and excess 5 did not precipitate during this isolation. Overall, the reaction could be performed in -1 flow in equivalent yield to batch conditions at 17 g h throughput using only an 18.5 mL reactor (Figure 4).
Figure 4. System diagram for the preparation of 2 in continuous flow.
Scheme 5. Origin of carbamoylguanidine impurity 7.
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30 s a white solid formed, which could be collected by filtration, washed with iPrOH (1 volume) and dried to give N,N’dicyclohexylurea 2 as a white solid: IR νmax (THF solution) -1 1 1704, 1689, 1417, 1372, 1193 cm ; H NMR (400 MHz, CDCl3) δ 4.60 (tt, J = 12.5, 3.5 Hz, 2H), 3.60 (s, 2H), 2.26 (qd, J = 12.5, 3.5 13 Hz, 4 H), 1.85 (m, 4H), 1.65 (m, 6H), 1.36 (m, 6H); C NMR (100 MHz, CDCl3) δ 165.0, 151.2, 55.1, 40.9, 29.0, 26.2, 25.0.
ASSOCIATED CONTENT Supporting Information Experimental procedures and analytical data for 5 and 7. Details of reaction monitoring techniques. This material is available free of charge at http://pubs.acs.org. In summary, the continuous preparation of 2 was enabled, and a strategy for handling insoluble DCHU by reaction with POCl3 was developed. An approach was demontrated where a reaction was transferred rapidly into continuous operation using small-scale batch experimentation, solubility measurements, parallel screening and in situ reaction monitoring. These data enabled optimization of the chemistry and provided insight into the mechanism of the structure, origin and fate of the soluble salt 5, including its role in impurity formation. This type of preliminary screening may be especially valuable if only small amounts of material are available for process development. Although other methods for the preparation of 2 were ultimately used at plant scale, the concept of handling insoluble solids in flow by reaction, derivatization or recycling may have wider application for the enabling of scalable continuous flow processes.
EXPERIMENTAL DETAILS Representative procedure for the preparation of 2 in continuous flow. The experiment was performed in a Syrris Asia flow reactor fitted with a PFA reactor coil (1.6 mm OD, 1.0 mm ID) and an un-heated Vapourtec acid-resistant back-pressure regulator cartridge. Feeds were switched using Swagelock 2way valves. Dry (4 h. The assay yield was determined by HPLC analysis of the concentration of 2 in the product stream. The 13 product 2 could be isolated by addition of the product stream (1 volume) to iPrOH (4 volumes) with stirring. After
AUTHOR INFORMATION Corresponding Author alexander.g.o’
[email protected] ACKNOWLEDGMENTS We are grateful to David Leitch and Gregg Barcan for helpful discussions, Robert Bondi for assistance with IR monitoring and John Starcevich for assistance with flow reactor operation.
REFERENCES (1) For methods not covered in this report, see: (a) Yogo, M.; Hirota, K.; Senda, S. Chem. Pharm. Bull. 1982, 30, 1333; (b) Poelma, S. O.; Oh, S. S.; Helmy, S.; Knight, A. S.; Burnett, G. L.; Soh, H. T.; Hawker, C. J.; de Alaniz, J. R. Chem. Commun. 2016, 52, 10525; (c) Graziano, M. L.; Cimminiello, G. Synthesis 1989, 54; (d) Mesropyan, E. G.; Ambartsumyan, G. B.; Avetisyan, A. A.; Galstyan, A. S.; Arutyunova, I. R. Russ. J. Org. Chem. 2005, 41, 67. (2) (a) Xia, G.; Benmohamed, R.; Kim, J.; Arvanited, A. C.; Morimoto, R. I.; Ferrante, R. J.; Kirsch, D. R.; Silverman, R. B. J. Med. Chem. 2011, 54, 2409; for related examples, see (b) Devi, I.; Bhuyan, P. J. Tetrahedron Lett. 2005, 46, 5727; (c) We also unsuccessfully studied the reaction of diethyl malonate with DCHU at high temperature. (3) (a) Bose, A. K.; Garrat, S. J. Am. Chem. Soc. 1962, 84, 1310; (b) Bose, A. K.; Garratt, S. Tetrahedron 1963, 19, 85. (4) (a) Chen, Y.; Sabio, J. C.; Hartman, R. L. J. Flow. Chem. 2015, 5, 166; (b) Hartman, R. L. Org. Process Res. Dev. 2012, 16, 870; (c) Deadman, B. J.; Browne, D. L.; Baxendale, I. R.; Ley, S. V. Chem. Eng. Technol. 2015, 38, 259; (d) Plutschack, M. B.; Pieber, B.; Gilmore, K.; Seeberger, P. H. Chem. Rev. 2017, 117, 11796; (e) Filipponi, P.; Gioiello, A.; Baxendale, I. R. Org. Process Res. Dev. 2016, 20, 371; (e) Noël, T. Topics in Organometallic Chemistry 2016, 57, 1. (5) Daneshfar, A.; Baghlani, M.; Sarabi, R. S.; Sahraei, R.; Abassi, S.; Kaviyan, H.; Khezeli, T. Fluid Ph. Equilibria 2012, 313, 11. (6) Albert, J. S.; Hamilton, A. D.; Hart, A. C.; Feng, X.; Lin, L.; Wang, Z. 1,3-Dicyclohexylcarbodiimide. e-EROS Encyclopedia of Reagents for Organic Synthesis 2017, 1. (7) (a) Findeisen, K.; Santel, H. J.; Luerssen, K.; Schmidt, R. R. Eur. Pat. Appl. 1991, 412358; (b) Ulrich, H.; Tilley, J. N.; Sayigh, A. A. R. J. Org. Chem. 1964, 29, 2401; (c) Eilingsfeld, H.; Neubauer, G.; Seefelder, M.; Weidincer, H. Chem. Ber. 1964, 97, 1232. (8) (a) Schlama, T.; Gouverneur, V.; Mioskowski, C. Tetrahedron Lett. 1996, 37, 7047; (b) Stevens, C. L.; Singhal, G. H.; Ash, A. B. J. Org. Chem. 1967, 32, 2895; (c) Budhathoki-Uprety, Novak, B. M. Macromolecules 2011, 44, 5947; (d) Sheehan, J.; Cruickshank, P.; Boshart, G. J. Org. Chem. 1961, 26, 2525; (e) Gao, X.; Zhang, Q. CN patent 101928237; (f) Maity, A. K.; Fortier, S.; Griego, L.; MettaMagaña, A. J. Inorg. Chem. 2014, 53, 8155.
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Organic Process Research & Development (9) Additional reagents were screened, that formed adducts with DCC: oxalyl chloride gave dichloroimidazolidinedione (Moerdyk, J. P; Bielawski, C. W. Chem. Eur. J. 2014, 20, 13487.); cyanuric chloride gave N-(2,4-dichloro-5-triazin-6-yl)-N-cyclohexyl-N'chloroformamidine. (10) Though chlorination of malonic acid is an alternative pathway, IR analysis of a mixture of malonic acid and POCl3 showed no conversion to malonyl chloride, even at elevated temperature (see supporting information). (11) As NMR showed a complex mixture of geometric isomers, the structure of 7 was determined by LC-MS and via preparation of an
authentic marker (Radau, M.; Hartke, K. Arch. Pharm. 1972, 305, 665). Isolated samples slowly decomposed to N,N’,N’’tricyclohexylguanidine. (12) Addition of either DCC or DCHU to 5 led to the formation of 7. (13) During development of this process, solutions of 2 were typically passed directly to downstream synthetic steps without workup, although samples of 2 were isolated for characterization by taking aliquots of the reactor output.
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Table of Contents graphic:
Keywords: Flow Chemistry; Reaction Monitoring; Dehydration
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