Scale-up and optimization of the synthesis of dual CBP/BRD4 inhibitor ISOX-DUAL.
Edmonds, Anthony K.; Oakes, Catherine S.; Hassell-Hart, Storm; Bruyère, Didier; Tizzard, Graham J.; Coles, Simon J.; Felix, Robert; Maple, Hannah J.; Marsh, Graham P.; Spencer, John; Organic & biomolecular chemistry 20 (2022) 4021–4029; doi:10.1039/d2ob00609j

data_7158656
_publ_section_title
;
 Scale-up and optimization of the synthesis of dual CBP/BRD4 inhibitor
 ISOX-DUAL.
;
_journal_issue                   19
_journal_name_full               'Organic &amp; biomolecular chemistry'
_journal_page_first              4021
_journal_page_last               4029
_journal_paper_doi               10.1039/d2ob00609j
_journal_volume                  20
_journal_year                    2022
_chemical_absolute_configuration ad
_chemical_formula_moiety         'C17 H21 N3 O4'
_chemical_formula_sum            'C17 H21 N3 O4'
_chemical_formula_weight         331.37
_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             2021-09-15
_audit_creation_method
;
Olex2 1.5
(compiled 2021.08.20 svn.r13c46975 for OlexSys, GUI svn.r6396)
;
_audit_update_record
;
2021-09-15 deposited with the CCDC.	2022-04-25 downloaded from the CCDC.
;
_cell_angle_alpha                90
_cell_angle_beta                 90
_cell_angle_gamma                90
_cell_formula_units_Z            8
_cell_length_a                   7.10820(10)
_cell_length_b                   14.5273(2)
_cell_length_c                   31.5780(5)
_cell_measurement_reflns_used    7713
_cell_measurement_temperature    100(2)
_cell_measurement_theta_max      69.9190
_cell_measurement_theta_min      3.3420
_cell_volume                     3260.84(8)
_computing_cell_refinement       'CrysAlisPro 1.171.40.47a (Rigaku OD, 2019)'
_computing_data_collection       'CrysAlisPro 1.171.40.47a (Rigaku OD, 2019)'
_computing_data_reduction        'CrysAlisPro 1.171.40.47a (Rigaku OD, 2019)'
_computing_molecular_graphics    'Olex2 1.5 (Dolomanov et al., 2009)'
_computing_publication_material  'Olex2 1.5 (Dolomanov et al., 2009)'
_computing_structure_refinement  'SHELXL 2018/3 (Sheldrick, 2015)'
_computing_structure_solution    'SHELXT 2018/2 (Sheldrick, 2018)'
_diffrn_ambient_environment      N~2~
_diffrn_ambient_temperature      100(2)
_diffrn_detector                 'hybrid pixel detector'
_diffrn_detector_area_resol_mean 10
_diffrn_detector_dtime           0.000
_diffrn_detector_type            'Rigaku, HyPix 6000'
_diffrn_measured_fraction_theta_full 0.999
_diffrn_measured_fraction_theta_max 0.992
_diffrn_measurement_details
;
List of Runs (angles in degrees, time in seconds):

  # Type    Start    End  Width  t~exp~   \w     \q     \k     \f   Frames
  1  \w    -84.00  94.00   0.50    0.50    --    5.00  20.00-150.00  356
  2  \w   -179.00  -1.00   0.50    2.00    --  -90.00  58.00  28.40  356
  3  \w   -179.00  -1.00   0.50    2.00    --  -90.00  59.00-109.15  356
  4  \w   -179.00  -1.00   0.50    2.00    --  -90.00  30.00 150.00  356
  5  \w   -179.00 -12.00   0.50    2.00    --  -90.00  58.00-142.44  334
  6  \w   -129.00 -21.00   0.50    2.00    --  -90.00  57.00 -84.21  216
  7  \w   -178.00  -3.00   0.50    2.00    --  -90.00  59.00 -45.22  350
;
_diffrn_measurement_device       'four-circle diffractometer'
_diffrn_measurement_device_details 'Rigaku, AFC11 quarter \c goniometer'
_diffrn_measurement_device_type
'Rigaku 007HF equipped with Varimax confocal mirrors and an AFC11 goniometer and HyPix 6000 detector'
_diffrn_measurement_method       'profile data from \w-scans'
_diffrn_measurement_specimen_support 'MiTeGen MicroLoop'
_diffrn_orient_matrix_type
'CrysAlisPro convention (1999,Acta A55,543-557)'
_diffrn_orient_matrix_UB_11      -0.0173646000
_diffrn_orient_matrix_UB_12      0.1055128000
_diffrn_orient_matrix_UB_13      -0.0028842000
_diffrn_orient_matrix_UB_21      -0.0096821000
_diffrn_orient_matrix_UB_22      0.0059834000
_diffrn_orient_matrix_UB_23      0.0486607000
_diffrn_orient_matrix_UB_31      0.2158099000
_diffrn_orient_matrix_UB_32      0.0088190000
_diffrn_orient_matrix_UB_33      0.0019704000
_diffrn_radiation_collimation    'Varimax focusing mirrors'
_diffrn_radiation_monochromator  mirror
_diffrn_radiation_probe          x-ray
_diffrn_radiation_type           'Cu K\a'
_diffrn_radiation_wavelength     1.54178
_diffrn_radiation_xray_symbol    K-L~3~
_diffrn_reflns_av_R_equivalents  0.0668
_diffrn_reflns_av_unetI/netI     0.0497
_diffrn_reflns_Laue_measured_fraction_full 0.999
_diffrn_reflns_Laue_measured_fraction_max 0.992
_diffrn_reflns_limit_h_max       8
_diffrn_reflns_limit_h_min       -7
_diffrn_reflns_limit_k_max       17
_diffrn_reflns_limit_k_min       -17
_diffrn_reflns_limit_l_max       37
_diffrn_reflns_limit_l_min       -38
_diffrn_reflns_number            30549
_diffrn_reflns_point_group_measured_fraction_full 0.999
_diffrn_reflns_point_group_measured_fraction_max 0.987
_diffrn_reflns_theta_full        67.679
_diffrn_reflns_theta_max         70.367
_diffrn_reflns_theta_min         2.799
_diffrn_source                   'Rotating anode'
_diffrn_source_current           30.0
_diffrn_source_power             1.2
_diffrn_source_target            Cu
_diffrn_source_type              'Rigaku 007 HF'
_diffrn_source_voltage           40.0
_exptl_absorpt_coefficient_mu    0.804
_exptl_absorpt_correction_T_max  1.00000
_exptl_absorpt_correction_T_min  0.61539
_exptl_absorpt_correction_type   multi-scan
_exptl_absorpt_process_details
;
CrysAlisPro 1.171.40.47a (Rigaku Oxford Diffraction, 2019)
Empirical absorption correction using spherical harmonics,
 implemented in SCALE3 ABSPACK scaling algorithm.
;
_exptl_crystal_colour            red
_exptl_crystal_colour_primary    red
_exptl_crystal_density_diffrn    1.350
_exptl_crystal_description       lath
_exptl_crystal_F_000             1408
_exptl_crystal_recrystallization_method
'The material was recrystallised from DCM by slow evaporation'
_exptl_crystal_size_max          0.3
_exptl_crystal_size_mid          0.07
_exptl_crystal_size_min          0.01
_refine_diff_density_max         0.264
_refine_diff_density_min         -0.349
_refine_diff_density_rms         0.072
_refine_ls_abs_structure_details
;
 Flack x determined using 2116 quotients [(I+)-(I-)]/[(I+)+(I-)]
 (Parsons, Flack and Wagner, Acta Cryst. B69 (2013) 249-259).
;
_refine_ls_abs_structure_Flack   -0.08(15)
_refine_ls_extinction_method     none
_refine_ls_goodness_of_fit_ref   1.086
_refine_ls_hydrogen_treatment    mixed
_refine_ls_matrix_type           full
_refine_ls_number_parameters     441
_refine_ls_number_reflns         6152
_refine_ls_number_restraints     1
_refine_ls_restrained_S_all      1.086
_refine_ls_R_factor_all          0.0592
_refine_ls_R_factor_gt           0.0533
_refine_ls_shift/su_max          0.000
_refine_ls_shift/su_mean         0.000
_refine_ls_structure_factor_coef Fsqd
_refine_ls_weighting_details
'w=1/[\s^2^(Fo^2^)+(0.0674P)^2^+0.9373P] where P=(Fo^2^+2Fc^2^)/3'
_refine_ls_weighting_scheme      calc
_refine_ls_wR_factor_gt          0.1274
_refine_ls_wR_factor_ref         0.1309
_reflns_Friedel_coverage         0.741
_reflns_Friedel_fraction_full    1.000
_reflns_Friedel_fraction_max     0.979
_reflns_number_gt                5507
_reflns_number_total             6152
_reflns_threshold_expression     'I > 2\s(I)'
_cod_data_source_file            d2ob00609j2.cif
_cod_data_source_block           18
_cod_depositor_comments
'Adding full bibliography for 7158654--7158659.cif.'
_cod_database_code               7158656
_shelx_shelxl_version_number     2018/3
_chemical_oxdiff_formula         'C17 H21 N3 O4 '
_chemical_oxdiff_usercomment     AKE-020
_shelx_estimated_absorpt_t_max   0.992
_shelx_estimated_absorpt_t_min   0.794
_olex2_refinement_description
;
1. Fixed Uiso
 At 1.2 times of:
  All C(H) groups, All C(H,H) groups, All N(H) groups
 At 1.5 times of:
  All C(H,H,H) groups
2. Restrained distances
 N52-H52 \\sim N2-H2
 with sigma of 0.02
3.a Secondary CH2 refined with riding coordinates:
 C58(H58A,H58B), C8(H8A,H8B), C12(H12A,H12B), C7(H7A,H7B), C59(H59A,H59B),
 C9(H9A,H9B), C62(H62A,H62B), C57(H57A,H57B), C60(H60A,H60B), C61(H61A,H61B),
 C10(H10A,H10B), C11(H11A,H11B)
3.b Aromatic/amide H refined with riding coordinates:
 C3(H3), C53(H53), C64(H64), C5(H5), C56(H56), C6(H6), C55(H55), C14(H14),
 C65(H65), C15(H15)
3.c Idealised Me refined as rotating group:
 C17(H17A,H17B,H17C), C67(H67A,H67B,H67C)
;
_shelx_res_checksum              10240
_olex2_date_sample_data_collection 2019-04-04
_olex2_date_sample_submission    2019-03-12
_olex2_diffrn_ambient_temperature_device 'Oxford Cryosystems'
_olex2_exptl_crystal_mounting_method
'The crystal was mounted on a MITIGEN holder in perfluoroether oil'
_olex2_submission_original_sample_id AKE-020
_olex2_submission_special_instructions 'No special instructions were received'
_oxdiff_exptl_absorpt_empirical_details
;
Empirical correction (ABSPACK) includes:
- Absorption correction using spherical harmonics
- Frame scaling
;
_oxdiff_exptl_absorpt_empirical_full_max 1.600
_oxdiff_exptl_absorpt_empirical_full_min 0.678