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_7158654
_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         'C16 H21 N5 O3'
_chemical_formula_sum            'C16 H21 N5 O3'
_chemical_formula_weight         331.38
_space_group_crystal_system      monoclinic
_space_group_IT_number           14
_space_group_name_Hall           '-P 2ybc'
_space_group_name_H-M_alt        'P 1 21/c 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                 116.058(12)
_cell_angle_gamma                90
_cell_formula_units_Z            4
_cell_length_a                   19.378(2)
_cell_length_b                   4.9594(2)
_cell_length_c                   18.3832(15)
_cell_measurement_reflns_used    4308
_cell_measurement_temperature    100(2)
_cell_measurement_theta_max      29.8620
_cell_measurement_theta_min      3.1440
_cell_volume                     1587.1(3)
_computing_cell_refinement       'CrysAlisPro 1.171.39.34b (Rigaku OD, 2017)'
_computing_data_collection       'CrysAlisPro 1.171.39.34b (Rigaku OD, 2017)'
_computing_data_reduction        'CrysAlisPro 1.171.39.34b (Rigaku OD, 2017)'
_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 2014/5 (Sheldrick, 2014)'
_diffrn_ambient_temperature      100(2)
_diffrn_detector                 'CCD area detector'
_diffrn_detector_area_resol_mean 28.5714
_diffrn_detector_dtime           0.000
_diffrn_detector_type            'Rigaku HG Saturn724+ (2x2 bin mode)'
_diffrn_measured_fraction_theta_full 0.999
_diffrn_measured_fraction_theta_max 0.998
_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    -99.00  15.00   1.00    7.50    --   -9.70 -38.00 -90.00  114
  2  \w    -99.00  15.00   1.00    7.50    --   -9.70 -38.00  30.00  114
  3  \w    -34.00  80.00   1.00    7.50    --   -9.70  38.00  60.00  114
  4  \w    -34.00  27.00   1.00    7.50    --   -9.70  38.00 -30.00   61
;
_diffrn_measurement_device       'four-circle \k goniometer'
_diffrn_measurement_device_details 'Rigaku, AFC12 \k goniometer'
_diffrn_measurement_device_type
'Rigaku FRE+ equipped with HF Varimax confocal mirrors and an AFC12 goniometer and HG Saturn 724+ 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      -0.0400934000
_diffrn_orient_matrix_UB_12      -0.0249403000
_diffrn_orient_matrix_UB_13      -0.0172665000
_diffrn_orient_matrix_UB_21      0.0028899000
_diffrn_orient_matrix_UB_22      -0.0794281000
_diffrn_orient_matrix_UB_23      -0.0306537000
_diffrn_orient_matrix_UB_31      0.0066380000
_diffrn_orient_matrix_UB_32      -0.1162516000
_diffrn_orient_matrix_UB_33      0.0246280000
_diffrn_radiation_collimation    0.2
_diffrn_radiation_monochromator  'Confocal mirrors, HF Varimax'
_diffrn_radiation_probe          x-ray
_diffrn_radiation_type           'Mo K\a'
_diffrn_radiation_wavelength     0.71073
_diffrn_radiation_xray_symbol    K-L~3~
_diffrn_reflns_av_R_equivalents  0.0585
_diffrn_reflns_av_unetI/netI     0.0538
_diffrn_reflns_Laue_measured_fraction_full 0.999
_diffrn_reflns_Laue_measured_fraction_max 0.998
_diffrn_reflns_limit_h_max       25
_diffrn_reflns_limit_h_min       -24
_diffrn_reflns_limit_k_max       6
_diffrn_reflns_limit_k_min       -6
_diffrn_reflns_limit_l_max       23
_diffrn_reflns_limit_l_min       -23
_diffrn_reflns_number            18992
_diffrn_reflns_point_group_measured_fraction_full 0.999
_diffrn_reflns_point_group_measured_fraction_max 0.998
_diffrn_reflns_theta_full        25.242
_diffrn_reflns_theta_max         27.481
_diffrn_reflns_theta_min         2.467
_diffrn_source                   'Rotating Anode'
_diffrn_source_current           55.0
_diffrn_source_power             2.475
_diffrn_source_target            Mo
_diffrn_source_type              'Rigaku FRE+'
_diffrn_source_voltage           45.0
_exptl_absorpt_coefficient_mu    0.099
_exptl_absorpt_correction_T_max  1.00000
_exptl_absorpt_correction_T_min  0.47335
_exptl_absorpt_correction_type   multi-scan
_exptl_absorpt_process_details
;
CrysAlisPro 1.171.39.34b (Rigaku Oxford Diffraction, 2017)
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    1.387
_exptl_crystal_description       plate
_exptl_crystal_F_000             704
_exptl_crystal_recrystallization_method
'The material was recrystallised from DCM by slow evaporation'
_exptl_crystal_size_max          0.18
_exptl_crystal_size_mid          0.16
_exptl_crystal_size_min          0.01
_refine_diff_density_max         0.256
_refine_diff_density_min         -0.340
_refine_diff_density_rms         0.057
_refine_ls_extinction_method     none
_refine_ls_goodness_of_fit_ref   1.038
_refine_ls_hydrogen_treatment    mixed
_refine_ls_matrix_type           full
_refine_ls_number_parameters     221
_refine_ls_number_reflns         3640
_refine_ls_number_restraints     0
_refine_ls_restrained_S_all      1.038
_refine_ls_R_factor_all          0.0878
_refine_ls_R_factor_gt           0.0542
_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^)+(0.0720P)^2^+0.1133P] where P=(Fo^2^+2Fc^2^)/3'
_refine_ls_weighting_scheme      calc
_refine_ls_wR_factor_gt          0.1249
_refine_ls_wR_factor_ref         0.1447
_reflns_Friedel_coverage         0.000
_reflns_number_gt                2475
_reflns_number_total             3640
_reflns_threshold_expression     'I > 2\s(I)'
_cod_data_source_file            d2ob00609j2.cif
_cod_data_source_block           15
_cod_depositor_comments
'Adding full bibliography for 7158654--7158659.cif.'
_cod_database_code               7158654
_shelx_shelxl_version_number     2018/3
_chemical_oxdiff_formula         'C16 H21 N5 O3'
_chemical_oxdiff_usercomment     AKE-017
_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.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)
2.b Aromatic/amide H refined with riding coordinates:
 C3(H3), C5(H5), C6(H6), C14(H14), C15(H15)
2.c Idealised Me refined as rotating group:
 C16(H16A,H16B,H16C)
;
_shelx_res_checksum              57636
_olex2_date_sample_data_collection 2018-02-07
_olex2_date_sample_submission    2018-01-26
_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-017
_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 2.303
_oxdiff_exptl_absorpt_empirical_full_min 0.693