Development of a scalable synthesis of a GPR40 receptor agonist

Organic Process Research and Development

Volumn 15, Issue 3, 2011, Pages 570-580

  Walker, Shawn D ^a   Borths, Christopher J ^a   Divirgilio, Evan ^a   Huang, Liang ^a   Liu, Pingli ^a   Morrison, Henry ^a   Sugi, Kiyoshi ^a   Tanaka, Masahide ^a   Woo, Jacqueline C S ^a   Faul, Margaret M ^a  

^a AMGEN INC   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ALKYNYLATIONS; ALKYNYLS; CHEMOSELECTIVE; CONVERGENT SYNTHESIS; DIHYDRATES; DIRECT COUPLING; DRUG SUBSTANCES; FREE ACIDS; IN-SITU; MELDRUM'S ACIDS; PHENOL ALKYLATION; PHYSIO-CHEMICAL; PROCESS DEVELOPMENT; RACEMIC ACIDS; SCALABLE SYNTHESIS; SODIUM SALT; SUZUKI-MIYAURA; SYNTHETIC ROUTES; TRIFLUOROMETHYL;

BROMINE COMPOUNDS; PHENOLS;

CHEMICAL REACTIONS;

EID: 79957517263     PISSN: 10836160     EISSN: 1520586X     Source Type: Journal    
DOI: 10.1021/op1003055     Document Type: Article

References (49)

1. Medina, J. C.; Houze, J. B. Annu. Rep. Med. Chem. 2008, 43, 75
2. Akerman, M.; Houze, J.; Lin, D. C. H.; Liu, J.; Luo, J.; Medina, J. C.; Qiu, W.; Reagan, J. D.; Sharma, R.; Shuttleworth, S. J.; Sun, Y.; Zhang, J.; Zhu, L. Chem. Abstr. 2005, 143, 326090; Patent WO/2005/086661 A2, 2005.
3. As a step to addressing this synthetic challenge we recently developed an asymmetric conjugate alkynylation of Meldrum's acid derived acceptors providing practical access to chiral β-alkynyl acids: Cui, S.; Walker, S. D.; Woo, J. C. S.; Borths, C. J.; Mukherjee, H.; Chen, M. J.; Faul, M. M. J. Am. Chem. Soc. 2010, 132, 436 For a discussion of enantioselective approaches to AMG 837, see: Woo, J. C. S.; Cui, S.; Walker, S. D.; Faul, M. M. Tetrahedron 2010, 66, 4730
4. Yazaki, R.; Kumagai, N.; Shibasaki, M. Org. Lett. 2011, 13, 952 For Cu-catalyzed alkynylation of Meldrum's acid derived acceptors with aryl acetylenes see: Knöpfel, T. F.; Carreira, E. M. J. Am. Chem. Soc. 2003, 125, 6054 For Rh-catalyzed alkynylation of Meldrum's acid derived acceptors with TMS-acetylenes see: Fillion, E.; Zorzitto, A. K. J. Am. Chem. Soc. 2009, 131, 14608 For recent reviews of asymmetric conjugate alkynylation, see: Fujimori, S.; Knöpfel, T. F.; Zarotti, P.; Ichikawa, T.; Boyall, D.; Carreira, E. M. Bull. Chem. Soc. Jpn. 2007, 80, 1635
5. Trost, B. M.; Weiss, A. H. Adv. Synth. Catal. 2009, 351, 963
6. Bigi, F; Carloni, S.; Farrari, L.; Maggi, A.; Satori, G. Tetrahedron 2001, 42, 5203
7. Miyashita, N.; Yoshikoshi, A.; Grieco, P. A. J. Org. Chem. 1977, 42, 3772
8. This presumably results from polymerization of DHP; see: Burrows, R. C. Polym. Prepr. 1965, 6, 600
9. Kuethe, J. T.; Tellers, D. M.; Weissman, S. A.; Yasuda, N. Org. Process Res. Dev. 2009, 13, 471
10. The efficiency of the classical resolution step was highly dependent on the purity of the starting racemic acid. Consequently, a target purity of >95% was established.
11. HPLC analysis indicated that <5% of Meldrum's acid hydrolyzed in water at 32°C after 2 h. In contrast, 48% hydrolyzed at 50 °C and >99% hydrolyzed at 79 °C over the same time period. Meldrum's acid is known to decompose to acetone and malonic acid in water: Kaczvinsky, J. R., Jr.; Read, S. A. J. Chromatogr. 1992, 575, 177
12. HPLC analysis indicated that 11% of 3 hydrolyzed in 1:1 acetone/water at room temperature after 1 h and 85% hydrolyzed after 16 h.
13. Reaction conversion in THF could be increased to 75% by adding 10 mol% DMAP to the mixture.
14. Product 3 readily agglomerated into beads in water that contained 10-20% vol of toluene. Agglomeration was not efficient in water that contained more than 20% or less than 5% toluene. For a discussion on agglomeration effects, see: Pietsch, W. Agglomeration in Industry; Wiley-VCH: Weinheim, 2005, Vols. 1 and 2. For a recent review of hydrophobic effects and reactions in/on water, see
15. Butler, R. N.; Coyne, A. G. Chem. Rev. 2010, 110, 6302
16. Since the next step employed a Grignard reagent, a target of <0.1% water was set.
17. Raman spectroscopy is particularly useful here since it is suitable for analysis of heterogeneous mixtures and is insensitive to aqueous solvents.
18. 3.
19. This was attributed to the low solubility of the phenoxide salts in THF. Addition of polar co-solvents (e.g., TMEDA, NMP, DMPU) did not improve conversions. Similar results were obtained using a TMS-ether protecting group.
20. -1.0 vol = 1.0 L/kg.
21. Solubility of N -methylmorpholine hydrochloride in THF at room temperature is <2 mg/mL as determined via turbidity measurements.
22. 1,4-Addition occurred with >95% chemoselectivity with this addition mode. However, when a solution of acetate 9 was added to a solution of propynylmagnesuim bromide, HPLC analysis indicated a mixture containing 54% 10, 20% 11 and 16% 9.
23. Although the saponification was typically complete in 1 h, stress tests indicated that the mixture could be aged for 24 h without loss of yield or purity. Apparently, formation of an enolate anion suppresses ester hydrolysis of the malonate moiety.
24. The level of bis-acid in the product was dependent on the heating time during distillative solvent switch from THF to toluene. Small levels of bis-acid 12 are not a concern since 12 is also decarboxylated to (±)-1 in the next step.
25. Dyer, U. C.; Shapland, P. D.; Tiffin, P. D. Tetrahedron Lett. 2001, 42, 1765
26. A 5 wt % charge of NEChemcat E-type Pd/C (50% wet containing 5% Pd, corresponding to 0.125 wt% Pd overall)
27. 3-THF solutions are known to decompose over time, particularly at room temperature and above. Thus, lots shipped or stored for extended periods at room temperature may have low borane titers and can accumulate pressure. See safety highlights in Atkins, W. J., Jr.; Burkhardt, E. R.; Matos, K. Org. Process Res. Dev. 2006, 10, 1292
28. Potyen, M.; Josyula, K. V. B.; Schuck, M.; Lu, S.; Gao, P.; Hewitt, C. Org. Process Res. Dev. 2007, 11, 210
29. Guercio, G.; Manzo, A. M.; Goodyear, M.; Bacchi, S.; Curti, S.; Provera, S. Org. Process Res. Dev. 2009, 13, 489
30. Lobben, P. C.; Leung, S.S-W.; Tummala, S. Org. Process Res. Dev 2004, 8, 1072 Initial exotherm results from deprotonation of acid 16 to form an acyloxyborane intermediate that accumulates at low temperature. The second exotherm during warming can be explained by the sequential reduction of this acyloxyborane intermediate to a trialkoxyboroxine which librates 17 upon aqueous workup.
31. 3.
32. 2 off-gases.
33. Relative Aldrich catalogue prices are illustrative. Aryl halides: 14, $1.7/g (25 g bottle); 19, $0.13/g (100 g bottle). Boronic acids: 15, $30/g (5 g bottle); 18, $14/g (10 g bottle).
34. 3-catalyzed SMC reactions, see: Kudo, N.; Perseghini, M.; Fu, G. C. Angew. Chem., Int. Ed. 2006, 45, 1282
35. 3 employed. Granular base was typically employed but faster reactions occurred with finer powder.
36. 3) is a mixture of keto-ester (91%) and its enol tautomer (∼9%) and is consistent with the measured LCMS M+ (428) value. For example, when a crude sample of neat 21 was allowed to stand open to air at room temperature for 17 h, 5.1% keto-ester was generated (HPLC assay).
37. The bromide 2 also has high solubility in many organic solvents including the subsequent crystallization solvents and was not detected in the API by HPLC assay.
38. At least half of the initial ethanol charge was distilled to prevent formation of an emulsion during the isopropyl acetate extraction.
39. Details and scope of this method have been reported elsewhere: Liu, P.; Huang, L.; Faul, M. M. Tetrahedron Lett. 2007, 48, 7380
40. Oxidative degradation (presumably via the intermediacy of a keto-acid) led to accumulation of a methyl ketone as the largest single impurity in aged samples of AMG 837. For example, when solid AMG 837 free acid was aged at 44 °C overnight (open air), ∼1% methyl ketone was detected by HPLC analysis. A solution of AMG 837 in acetonitrile (5 vol) at room temperature for 1 week accumulated 4% methyl ketone.
41. For a detailed discussion of salt screening for AMG 837, see: Morrison, H.; Jona, J.; Walker, S. D.; Woo, J. C. S.; Li, L.; Fang, J. Org. Process Res. Dev. 2011, 15, 104
42. Crystallization studies using focused beam reflectance measurements (FBRM, Lastentec) indicated significant particle attrition under high sheer agitation resulting in increased fines and poor filtration rates. To ensure good filtration on scale, the agitation should be reduced to maintain just-suspended solids after complete addition of NaOH and acetonitrile antisolvent.
43. Upon oven drying, initial acetonitrile levels in the wet cakes (typically 20-30 wt %) rapidly decreased but remained steady at ∼8 wt %, consistent with the theoretical monosolvate value.
44. Analytical samples of the conjugated diene degradation products were isolated by HPLC and their structures determined by 1D and 2D NMR analyses and HRMS. Related thermal and base-mediated prototropic rearrangements of acetylenic compounds to conjugated dienes have been reported: Jones, E. R. H.; Mansfield, E. H.; Whiting, M. C. J. Chem. Soc. 1954, 3208 For a review see: Iwai, I. Mechanisms of Molecular Migrations; Interscience: New York, 1969; Vol. 2.
45. The sodium salt is hygroscopic above 55% relative humidity (RH) with >30 wt% gain up to 95% RH by vapor sorption analysis. Static drying times on an Aurora filter varied from 2 days to >1 week depending on the batch and filter size. Bench-top modeling of unit operations (50-500 g scale pilots), indicated drying cycle times could be reduced using a rotary (<50 h) or fluid bed dryer (<5 h).
46. LCAP = liquid chromatography area percent.
47. For a report describing online humidity analysis during factory drying of a hydrate, see: Cypes, S. H.; Wenslow, R. M.; Thomas, S. M.; Chen, A. M.; Dorwart, J. G.; Corte, J. R.; Kaba, M. Org. Process Res. Dev. 2004, 8, 576
48. Typically, the hemicalcium salt wet cake contained ∼14 wt% water (by KF titration) before drying.
49. A multivariate curve resolution (MCR) method based on second derivative Raman measurements of the pure crystalline and amorphous forms was used. For full details, see: Xie, Y.; Tao, W.; Morrison, H.; Chiu, R.; Jona, J.; Fang, J.; Cauchon, N. Int. J. Pharm. 2008, 362, 29