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_7158655
_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 H19 N3 O3 S'
_chemical_formula_sum            'C16 H19 N3 O3 S'
_chemical_formula_weight         333.40
_space_group_crystal_system      triclinic
_space_group_IT_number           2
_space_group_name_Hall           '-P 1'
_space_group_name_H-M_alt        'P -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                74.263(2)
_cell_angle_beta                 85.817(2)
_cell_angle_gamma                76.699(2)
_cell_formula_units_Z            4
_cell_length_a                   7.2068(2)
_cell_length_b                   15.1888(3)
_cell_length_c                   15.2406(2)
_cell_measurement_reflns_used    31305
_cell_measurement_temperature    100(2)
_cell_measurement_theta_max      70.2840
_cell_measurement_theta_min      3.0010
_cell_volume                     1562.57(6)
_computing_cell_refinement       'CrysAlisPro 1.171.39.46b (Rigaku OD, 2018)'
_computing_data_collection       'CrysAlisPro 1.171.39.46b (Rigaku OD, 2018)'
_computing_data_reduction        'CrysAlisPro 1.171.39.46b (Rigaku OD, 2018)'
_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_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 0.992
_diffrn_measured_fraction_theta_max 0.990
_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    -89.00  89.00   0.50    0.50    --    0.00  60.00-120.00  356
  2  \w    -89.00  89.00   0.50    0.50    --    0.00  43.00   0.00  356
  3  \w   -179.00  -1.00   0.50    2.00    --  -90.00  29.00 120.00  356
  4  \w   -179.00  -1.00   0.50    2.00    --  -90.00  60.00-150.00  356
  5  \w   -179.00  -1.00   0.50    2.00    --  -90.00  57.00  30.00  356
  6  \w   -179.00  -1.00   0.50    2.00    --  -90.00  60.00  90.00  356
  7  \w   -179.00  -1.00   0.50    2.00    --  -90.00  60.00 -90.00  356
  8  \w   -179.00  -1.00   0.50    2.00    --  -90.00  60.00 -90.00  356
  9  \w   -179.00  -1.00   0.50    2.00    --  -90.00  14.00 -60.00  356
 10  \w   -179.00  -1.00   0.50    2.00    --  -90.00  60.00-150.00  356
 11  \w   -179.00  -1.00   0.50    2.00    --  -90.00  60.00 -30.00  356
 12  \w   -179.00  -1.00   0.50    2.00    --  -90.00  43.00-120.00  356
 13  \w   -179.00  -1.00   0.50    2.00    --  -90.00  29.00  30.00  356
 14  \w   -179.00  -1.00   0.50    2.00    --  -90.00  60.00-180.00  356
 15  \w   -179.00  -1.00   0.50    2.00    --  -90.00  60.00 -60.00  356
 16  \w   -179.00  -1.00   0.50    2.00    --  -90.00  60.00 120.00  356
 17  \w    -89.00  89.00   0.50    0.50    --    0.00  14.00  30.00  356
 18  \w    -89.00  27.00   0.50    0.50    --    0.00  29.00-150.00  232
 19  \w    -89.00  89.00   0.50    0.50    --    0.00  57.00 -60.00  356
;
_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      -0.0269075000
_diffrn_orient_matrix_UB_12      0.0008362000
_diffrn_orient_matrix_UB_13      0.1010044000
_diffrn_orient_matrix_UB_21      0.0829128000
_diffrn_orient_matrix_UB_22      -0.1064671000
_diffrn_orient_matrix_UB_23      0.0287822000
_diffrn_orient_matrix_UB_31      0.2016363000
_diffrn_orient_matrix_UB_32      0.0181160000
_diffrn_orient_matrix_UB_33      0.0003554000
_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  0.0411
_diffrn_reflns_av_unetI/netI     0.0226
_diffrn_reflns_Laue_measured_fraction_full 0.992
_diffrn_reflns_Laue_measured_fraction_max 0.990
_diffrn_reflns_limit_h_max       8
_diffrn_reflns_limit_h_min       -8
_diffrn_reflns_limit_k_max       18
_diffrn_reflns_limit_k_min       -18
_diffrn_reflns_limit_l_max       18
_diffrn_reflns_limit_l_min       -18
_diffrn_reflns_number            28801
_diffrn_reflns_point_group_measured_fraction_full 0.992
_diffrn_reflns_point_group_measured_fraction_max 0.990
_diffrn_reflns_theta_full        67.679
_diffrn_reflns_theta_max         68.239
_diffrn_reflns_theta_min         3.013
_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    2.010
_exptl_absorpt_correction_T_max  1.00000
_exptl_absorpt_correction_T_min  0.81051
_exptl_absorpt_correction_type   multi-scan
_exptl_absorpt_process_details
;
CrysAlisPro 1.171.39.46b (Rigaku Oxford Diffraction, 2018)
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    1.417
_exptl_crystal_description       block
_exptl_crystal_F_000             704
_exptl_crystal_recrystallization_method
'The material was recrystallised from a mixture of DCM and hexane  by slow evaporation'
_exptl_crystal_size_max          0.2
_exptl_crystal_size_mid          0.09
_exptl_crystal_size_min          0.07
_refine_diff_density_max         0.207
_refine_diff_density_min         -0.315
_refine_diff_density_rms         0.051
_refine_ls_extinction_method     none
_refine_ls_goodness_of_fit_ref   1.123
_refine_ls_hydrogen_treatment    mixed
_refine_ls_matrix_type           full
_refine_ls_number_parameters     495
_refine_ls_number_reflns         5671
_refine_ls_number_restraints     1040
_refine_ls_restrained_S_all      1.035
_refine_ls_R_factor_all          0.0377
_refine_ls_R_factor_gt           0.0362
_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^)+(0.0561P)^2^+0.5921P] where P=(Fo^2^+2Fc^2^)/3'
_refine_ls_weighting_scheme      calc
_refine_ls_wR_factor_gt          0.1028
_refine_ls_wR_factor_ref         0.1054
_reflns_Friedel_coverage         0.000
_reflns_number_gt                5314
_reflns_number_total             5671
_reflns_threshold_expression     'I > 2\s(I)'
_cod_data_source_file            d2ob00609j2.cif
_cod_data_source_block           17
_cod_depositor_comments
'Adding full bibliography for 7158654--7158659.cif.'
_cod_database_code               7158655
_shelx_shelxl_version_number     2018/3
_chemical_oxdiff_formula         'C16 H19 N3 O3 S'
_chemical_oxdiff_usercomment     AKE-019
_shelx_estimated_absorpt_t_max   0.872
_shelx_estimated_absorpt_t_min   0.689
_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. Restrained distances
 N52-H52 = N2-H2
 0.86 with sigma of 0.01
 C15A-C16A \\sim C15B-C16B
 with sigma of 0.02
 C13-C15A \\sim C13-C15B
 with sigma of 0.04
 C13-C16A \\sim C13-C16B
 with sigma of 0.04
 C65A-C66A \\sim C65B-C66B
 with sigma of 0.02
 C63-C65A \\sim C63-C65B
 with sigma of 0.04
 C63-C66A \\sim C63-C66B
 with sigma of 0.04
 S1A-C13 \\sim S1B-C13
 with sigma of 0.02
 S1A-C16A \\sim S1B-C16B
 with sigma of 0.02
 C14A-C13 \\sim C14B-C13
 with sigma of 0.02
 C14A-C15A \\sim C14B-C15B
 with sigma of 0.02
 S1A-C15A \\sim S1B-C15B
 with sigma of 0.04
 C14A-C16A \\sim C14B-C16B
 with sigma of 0.04
 S51A-C63 \\sim S51B-C63
 with sigma of 0.02
 S51A-C66A \\sim S51B-C66B
 with sigma of 0.02
 C64A-C63 \\sim C64B-C63
 with sigma of 0.02
 C64A-C65A \\sim C64B-C65B
 with sigma of 0.02
 S51A-C65A \\sim S51B-C65B
 with sigma of 0.04
 C64A-C66A \\sim C64B-C66B
 with sigma of 0.04
3. Rigid bond restraints
 All non-hydrogen atoms
 with sigma for 1-2 distances of 0.01 and sigma for 1-3 distances of 0.01
4. Uiso/Uaniso restraints and constraints
All non-hydrogen atoms have similar U: within 2A with sigma of 0.04 and sigma
for terminal atoms of 0.08 within 2A
5. Rigid body (RIGU) restrains
 All non-hydrogen atoms
 with sigma for 1-2 distances of 0.004 and sigma for 1-3 distances of 0.004
 S51B, C64A, C63, C64B, S51A, C65B, C66A, C66B, C65A, C13, C14B, S1A, C15B,
 C16A, C15A, C16B, S1B, C14A
 with sigma for 1-2 distances of 0.001 and sigma for 1-3 distances of 0.001
6. Others
 Sof(S1B)=Sof(C14B)=Sof(H14B)=Sof(C15B)=Sof(H15B)=Sof(C16B)=Sof(H16B)=1-FVAR(1)
 Sof(S1A)=Sof(C14A)=Sof(H14A)=Sof(C15A)=Sof(H15A)=Sof(C16A)=Sof(H16A)=FVAR(1)
 Sof(S51B)=Sof(C64B)=Sof(H64B)=Sof(C65B)=Sof(H65B)=Sof(C66B)=Sof(H66B)=1-FVAR(2)
 Sof(S51A)=Sof(C64A)=Sof(H64A)=Sof(C65A)=Sof(H65A)=Sof(C66A)=Sof(H66A)=FVAR(2)
7.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), C59(H59A,H59B), C60(H60A,H60B),
  C61(H61A,H61B), C62(H62A,H62B)
7.b Aromatic/amide H refined with riding coordinates:
 C3(H3), C6(H6), C5(H5), C14A(H14A), C14B(H14B), C15A(H15A), C15B(H15B),
 C16A(H16A), C16B(H16B), C53(H53), C56(H56), C55(H55), C64A(H64A), C64B(H64B),
 C65A(H65A), C65B(H65B), C66A(H66A), C66B(H66B)
;
_shelx_res_checksum              58760
_olex2_date_sample_data_collection 2018-06-08
_olex2_date_sample_submission    2018-05-16
_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-019
_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 1.818
_oxdiff_exptl_absorpt_empirical_full_min 0.696