Continuous Process Improvement in the Manufacture of Carfilzomib, Part 2: An Improved Process for Synthesis of the Epoxyketone Warhead
Beaver, Matthew G.; Shi, Xianqing; Riedel, Jan; Patel, Parth; Zeng, Alicia; Corbett, Michael T.; Robinson, Jo Anna; Parsons, Andrew T.; Cui, Sheng; Baucom, Kyle; Lovette, Michael A.; Içten, Elçin; Brown, Derek B.; Allian, Ayman; Flick, Tawnya G.; Chen, Wendy; Yang, Ning; Walker, Shawn D.; Organic Process Research & Development 24 (2020) 490–499; doi:10.1021/acs.oprd.0c00052

data_1557721
_publ_section_title
;
 Continuous Process Improvement in the Manufacture of Carfilzomib, Part 2:
 An Improved Process for Synthesis of the Epoxyketone Warhead
;
_journal_issue                   4
_journal_name_full               'Organic Process Research &amp; Development'
_journal_page_first              490
_journal_page_last               499
_journal_paper_doi               10.1021/acs.oprd.0c00052
_journal_volume                  24
_journal_year                    2020
_chemical_absolute_configuration ad
_chemical_formula_moiety         'C29 H38 F3 Mn N6 O4 S, C F3 O3 S, C2 H3 N'
_chemical_formula_sum            'C32 H41 F6 Mn N7 O7 S2'
_chemical_formula_weight         868.78
_space_group_crystal_system      orthorhombic
_space_group_IT_number           19
_space_group_name_Hall           'P 2ac 2ab'
_space_group_name_H-M_alt        'P 21 21 21'
_atom_sites_solution_hydrogens   mixed
_atom_sites_solution_primary     dual
_audit_creation_date             2017-08-28
_audit_creation_method
;
Olex2 1.2-alpha
(compiled 2017.08.10 svn.r3458 for OlexSys, GUI svn.r5381)
;
_cell_angle_alpha                90
_cell_angle_beta                 90
_cell_angle_gamma                90
_cell_formula_units_Z            4
_cell_length_a                   9.2868(2)
_cell_length_b                   18.0311(3)
_cell_length_c                   22.9054(4)
_cell_measurement_reflns_used    9866
_cell_measurement_temperature    173(2)
_cell_measurement_theta_max      28.07
_cell_measurement_theta_min      2.26
_cell_volume                     3835.54(12)
_computing_cell_refinement       'SAINT v8.34A (Bruker, 2013)'
_computing_data_collection       'COSMO (BRUKER, V1.61, 2009)'
_computing_data_reduction        'SAINT v8.34A (Bruker, 2013)'
_computing_molecular_graphics    'Olex2 (Dolomanov et al., 2009)'
_computing_publication_material  'Olex2 (Dolomanov et al., 2009)'
_computing_structure_refinement  'XL (Sheldrick, 2008)'
_computing_structure_solution    'ShelXT (Sheldrick, 2015)'
_diffrn_ambient_temperature      173(2)
_diffrn_detector_area_resol_mean 8.36
_diffrn_measured_fraction_theta_full 1.000
_diffrn_measured_fraction_theta_max 0.998
_diffrn_measurement_device_type  'Bruker APEX-II CCD'
_diffrn_measurement_method       \w
_diffrn_radiation_monochromator  graphite
_diffrn_radiation_type           MoK\a
_diffrn_radiation_wavelength     0.71073
_diffrn_reflns_av_R_equivalents  0.0704
_diffrn_reflns_av_unetI/netI     0.0655
_diffrn_reflns_Laue_measured_fraction_full 1.000
_diffrn_reflns_Laue_measured_fraction_max 0.998
_diffrn_reflns_limit_h_max       12
_diffrn_reflns_limit_h_min       -12
_diffrn_reflns_limit_k_max       22
_diffrn_reflns_limit_k_min       -24
_diffrn_reflns_limit_l_max       30
_diffrn_reflns_limit_l_min       -30
_diffrn_reflns_number            41896
_diffrn_reflns_point_group_measured_fraction_full 1.000
_diffrn_reflns_point_group_measured_fraction_max 0.995
_diffrn_reflns_theta_full        25.242
_diffrn_reflns_theta_max         28.303
_diffrn_reflns_theta_min         1.437
_diffrn_source                   'sealed tube'
_diffrn_standards_number         0
_exptl_absorpt_coefficient_mu    0.537
_exptl_absorpt_correction_T_max  0.7457
_exptl_absorpt_correction_T_min  0.6759
_exptl_absorpt_correction_type   multi-scan
_exptl_absorpt_process_details
'SADABS-2014/5 (Bruker,2014/5) was used for absorption correction. wR2(int) was 0.0734 before and 0.0692 after correction. The Ratio of minimum to maximum transmission is 0.9064. The \l/2 correction factor is 0.00150.'
_exptl_crystal_colour            colourless
_exptl_crystal_colour_primary    colourless
_exptl_crystal_density_diffrn    1.504
_exptl_crystal_description       chunk
_exptl_crystal_F_000             1796
_exptl_crystal_recrystallization_method 'used as received'
_exptl_crystal_size_max          0.257
_exptl_crystal_size_mid          0.198
_exptl_crystal_size_min          0.138
_refine_diff_density_max         0.981
_refine_diff_density_min         -0.647
_refine_diff_density_rms         0.072
_refine_ls_abs_structure_details
;
 Flack x determined using 2683 quotients [(I+)-(I-)]/[(I+)+(I-)]
 (Parsons, Flack and Wagner, Acta Cryst. B69 (2013) 249-259).
;
_refine_ls_abs_structure_Flack   -0.011(12)
_refine_ls_extinction_method     none
_refine_ls_goodness_of_fit_ref   1.056
_refine_ls_hydrogen_treatment    constr
_refine_ls_matrix_type           full
_refine_ls_number_parameters     554
_refine_ls_number_reflns         9493
_refine_ls_number_restraints     111
_refine_ls_restrained_S_all      1.055
_refine_ls_R_factor_all          0.0750
_refine_ls_R_factor_gt           0.0543
_refine_ls_shift/su_max          0.001
_refine_ls_shift/su_mean         0.000
_refine_ls_structure_factor_coef Fsqd
_refine_ls_weighting_details
'w=1/[\s^2^(Fo^2^)+(0.0794P)^2^+0.2087P] where P=(Fo^2^+2Fc^2^)/3'
_refine_ls_weighting_scheme      calc
_refine_ls_wR_factor_gt          0.1332
_refine_ls_wR_factor_ref         0.1480
_reflns_Friedel_coverage         0.792
_reflns_Friedel_fraction_full    1.000
_reflns_Friedel_fraction_max     0.992
_reflns_number_gt                7282
_reflns_number_total             9493
_reflns_threshold_expression     'I > 2\s(I)'
_cod_data_source_file            op0c00052_si_002.cif
_cod_data_source_block           agx817d
_cod_depositor_comments
;Adding full bibliography for 1557721.cif.

 Adding full bibliography for 1557721.cif.
;
_cod_database_code               1557721
_shelxl_version_number           2014/6
_shelx_estimated_absorpt_t_max   0.930
_shelx_estimated_absorpt_t_min   0.874
_olex2_refinement_description
;
1. Fixed Uiso
 At 1.2 times of:
  All C(H) groups, All C(H,H) groups
 At 1.5 times of:
  All C(H,H,H) groups, All O(H,H) groups
2. Restrained distances
 S2-O5 \\sim S2-O6 \\sim S2-O7
 with sigma of 0.04
 F5-F6 \\sim F6-F4 \\sim F5-F4
 with sigma of 0.04
 C32-F5 \\sim C32-F6 \\sim C32-F4
 with sigma of 0.04
 F5A-F6A \\sim F6A-F4A \\sim F5A-F4A
 with sigma of 0.04
 S2A-O5A \\sim S2A-O6A \\sim S2A-O7A
 with sigma of 0.04
3. Uiso/Uaniso restraints and constraints
O6A \\sim O7: within 2A with sigma of 0.01 and sigma for terminal atoms of 0.02
Uanis(F4) = Uanis(F5A)
Uanis(C32A) = Uanis(C31)
Uanis(C32) = Uanis(C27)
4. Rigid body (RIGU) restrains
 S2, F4, F5, F6, O5, O6, C32
 with sigma for 1-2 distances of 0.04 and sigma for 1-3 distances of 0.04
 S2A, F4A, F5A, F6A, O5A, O6A, C32A
 with sigma for 1-2 distances of 0.04 and sigma for 1-3 distances of 0.04
5. Others
 Fixed Sof: S2A(0.5) F4A(0.5) F5A(0.5) F6A(0.5) O5A(0.5) O6A(0.5) O7A(0.5)
 C32A(0.5) S2(0.5) F4(0.5) F5(0.5) F6(0.5) O5(0.5) O6(0.5) O7(0.5) C32(0.5)
6.a Rotating group:
 O1(H1A,H1B)
6.b Ternary CH refined with riding coordinates:
 C14(H14), C15(H15)
6.c Secondary CH2 refined with riding coordinates:
 C8(H8A,H8B), C10(H10A,H10B), C11(H11A,H11B), C12(H12A,H12B), C13(H13A,H13B),
 C16(H16A,H16B), C17(H17A,H17B), C18(H18A,H18B), C19(H19A,H19B), C27(H27A,H27B)
6.d Aromatic/amide H refined with riding coordinates:
 C3(H3), C4(H4), C5(H5), C6(H6), C23(H23), C24(H24), C25(H25), C26(H26)
6.e Idealised Me refined as rotating group:
 C9(H9A,H9B,H9C), C28(H28A,H28B,H28C), C30(H30A,H30B,H30C)
;
_olex2_diffrn_ambient_temperature_device 'Oxford Cryosystems'
_olex2_exptl_crystal_mounting_method
'The crystal was mounted on a nylon loop with paratone oil'
_olex2_submission_original_sample_id jbalsamo_01-75-3
_olex2_submission_special_instructions 'No special instructions were received'