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_7158659
_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_formula_moiety         'C17 H19 F N4 O3'
_chemical_formula_sum            'C17 H19 F N4 O3'
_chemical_formula_weight         346.36
_space_group_crystal_system      monoclinic
_space_group_IT_number           14
_space_group_name_Hall           '-P 2yn'
_space_group_name_H-M_alt        'P 1 21/n 1'
_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                 102.7490(10)
_cell_angle_gamma                90
_cell_formula_units_Z            8
_cell_length_a                   14.59320(10)
_cell_length_b                   7.25830(10)
_cell_length_c                   31.5918(4)
_cell_measurement_reflns_used    15025
_cell_measurement_temperature    100(2)
_cell_measurement_theta_max      69.8190
_cell_measurement_theta_min      2.8900
_cell_volume                     3263.76(7)
_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 0.991
_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   -142.00  37.00   0.50    0.75    --  -52.30  55.00-100.00  358
  2  \w    -75.00 -26.00   0.50    3.00    --  -90.00  55.00-100.00   98
  3  \w   -173.00 -90.00   0.50    3.00    --  -90.00  55.00-100.00  166
  4  \w    -19.00   6.00   0.50    0.75    --    5.00  55.00-100.00   50
  5  \w    -83.00  91.00   0.50    0.75    --    5.00   0.00-180.00  348
  6  \w   -157.00-123.00   0.50    3.00    --  -90.00  49.00-180.00   68
  7  \w   -153.00  -2.00   0.50    3.00    --  -90.00  20.00 -30.00  302
  8  \w   -170.00-136.00   0.50    3.00    --  -90.00  30.00 120.00   68
  9  \w    -55.00 -29.00   0.50    3.00    --  -90.00  30.00 120.00   52
 10  \w   -143.00 -94.00   0.50    3.00    --  -90.00  39.00-120.00   98
 11  \w   -178.00-152.00   0.50    3.00    --  -90.00  39.00-120.00   52
 12  \w    -57.00 -15.00   0.50    3.00    --  -90.00  39.00-120.00   84
 13  \w   -112.00  -1.00   0.50    3.00    --  -90.00  49.00-180.00  222
 14  \w   -174.00-144.00   0.50    3.00    --  -90.00  10.00 120.00   60
 15  \w    -43.00  -2.00   0.50    3.00    --  -90.00  10.00 120.00   82
 16  \w   -162.00  -2.00   0.50    3.00    --  -90.00  49.00 -60.00  320
 17  \w   -105.00 -22.00   0.50    3.00    --  -90.00  30.00   0.00  166
;
_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      0.0629723000
_diffrn_orient_matrix_UB_12      0.1704814000
_diffrn_orient_matrix_UB_13      0.0001031000
_diffrn_orient_matrix_UB_21      -0.0023405000
_diffrn_orient_matrix_UB_22      -0.0304395000
_diffrn_orient_matrix_UB_23      -0.0484909000
_diffrn_orient_matrix_UB_31      -0.0880123000
_diffrn_orient_matrix_UB_32      0.1226360000
_diffrn_orient_matrix_UB_33      -0.0121947000
_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  0.0296
_diffrn_reflns_av_unetI/netI     0.0247
_diffrn_reflns_Laue_measured_fraction_full 0.999
_diffrn_reflns_Laue_measured_fraction_max 0.991
_diffrn_reflns_limit_h_max       16
_diffrn_reflns_limit_h_min       -17
_diffrn_reflns_limit_k_max       8
_diffrn_reflns_limit_k_min       -8
_diffrn_reflns_limit_l_max       38
_diffrn_reflns_limit_l_min       -31
_diffrn_reflns_number            31409
_diffrn_reflns_point_group_measured_fraction_full 0.999
_diffrn_reflns_point_group_measured_fraction_max 0.991
_diffrn_reflns_theta_full        67.679
_diffrn_reflns_theta_max         70.052
_diffrn_reflns_theta_min         3.119
_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    0.893
_exptl_absorpt_correction_T_max  1.00000
_exptl_absorpt_correction_T_min  0.75437
_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            orange
_exptl_crystal_colour_primary    orange
_exptl_crystal_density_diffrn    1.410
_exptl_crystal_description       plate
_exptl_crystal_F_000             1456
_exptl_crystal_recrystallization_method
'The material was recrystallised from DCM by slow evaporation'
_exptl_crystal_size_max          0.12
_exptl_crystal_size_mid          0.1
_exptl_crystal_size_min          0.02
_refine_diff_density_max         0.218
_refine_diff_density_min         -0.306
_refine_diff_density_rms         0.047
_refine_ls_extinction_method     none
_refine_ls_goodness_of_fit_ref   1.117
_refine_ls_hydrogen_treatment    mixed
_refine_ls_matrix_type           full
_refine_ls_number_parameters     457
_refine_ls_number_reflns         6140
_refine_ls_number_restraints     0
_refine_ls_restrained_S_all      1.117
_refine_ls_R_factor_all          0.0460
_refine_ls_R_factor_gt           0.0424
_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^)+(0.0263P)^2^+3.4647P] where P=(Fo^2^+2Fc^2^)/3'
_refine_ls_weighting_scheme      calc
_refine_ls_wR_factor_gt          0.1036
_refine_ls_wR_factor_ref         0.1054
_reflns_Friedel_coverage         0.000
_reflns_number_gt                5663
_reflns_number_total             6140
_reflns_threshold_expression     'I > 2\s(I)'
_cod_data_source_file            d2ob00609j2.cif
_cod_data_source_block           20
_cod_depositor_comments
'Adding full bibliography for 7158654--7158659.cif.'
_cod_database_code               7158659
_shelx_shelxl_version_number     2018/3
_chemical_oxdiff_formula         'C17 H16 F N4 O3'
_chemical_oxdiff_usercomment     AKE-052
_shelx_estimated_absorpt_t_max   0.982
_shelx_estimated_absorpt_t_min   0.900
_olex2_refinement_description
;
1. Fixed Uiso
 At 1.2 times of:
  All C(H) groups, All C(H,H) groups, All N(H) groups
2.a Secondary CH2 refined with riding coordinates:
 C7(H7A,H7B), C8(H8A,H8B), C9(H9A,H9B), C10(H10A,H10B), C11(H11A,H11B),
 C12(H12A,H12B), C57(H57A,H57B), C58(H58A,H58B), C62(H62A,H62B), C61(H61A,H61B),
  C60(H60A,H60B), C59(H59A,H59B)
2.b Aromatic/amide H refined with riding coordinates:
 C3(H3), C5(H5), C6(H6), C17(H17), C15(H15), C14(H14), C53(H53), C55(H55),
 C56(H56), C67(H67), C65(H65), C64(H64)
;
_shelx_res_checksum              52992
_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-052
_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 1.761
_oxdiff_exptl_absorpt_empirical_full_min 0.808