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[ CAS No. 96-49-1 ] {[proInfo.proName]}

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Chemical Structure| 96-49-1
Chemical Structure| 96-49-1
Structure of 96-49-1 * Storage: {[proInfo.prStorage]}
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Product Citations

Abraha, Yuel W. ; Tsai, Chih-Wei ; Langner, Ernst H. G. DOI:

Abstract: Zeolitic Imidazolate Frameworks (ZIFs) and ZIF derivatives can catalyze the fixation of CO2 with epoxide substrates. Herein, we report a De Novo (direct mixing) synthesis method to produce nano-sized Zn- and Co-based Multi-Linker ZIFs (termed as ML-ZIFs) with polar 2-mercaptoimidazolate (SHIm) and non-polar 2-methylimidazolate (mIm) linkers, characterized by PXRD, TGA, TEM, 1H NMR, N2 and CO2 isotherms. All the ML-ZIFs have sodalite (SOD) topologies with permanent porosity and thermal stability of up to 250 °C. Both Zn- and Co-based ML-ZIFs were efficient in the fixation of CO2 with epichlorohydrin (ECH) and propylene-oxide (PrO) substrates without co-catalyst, showing improved catalytic activity over their single-linker counterparts (ZIF-8 and ZIF-67). ML-ZIF 5Co (with Co metal center and Co(mIm)1.68(SHIm)0.32 composition) showed a maximum Turn-Over Frequency (TOF) of 893 and 787 h-1 for CO2 fixation with PrO and ECH, respectively.

Keywords: Multi-linker frameworks ; Zeolitic imidazolate frameworks (ZIFs) ; Epoxides ; CO2 fixation ; Cycloaddition ; Catalysis

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Product Details of [ 96-49-1 ]

CAS No. :96-49-1 MDL No. :MFCD00005382
Formula : C3H4O3 Boiling Point : -
Linear Structure Formula :- InChI Key :KMTRUDSVKNLOMY-UHFFFAOYSA-N
M.W : 88.06 Pubchem ID :7303
Synonyms :

Calculated chemistry of [ 96-49-1 ]      Expand+

Physicochemical Properties

Num. heavy atoms : 6
Num. arom. heavy atoms : 0
Fraction Csp3 : 0.67
Num. rotatable bonds : 0
Num. H-bond acceptors : 3.0
Num. H-bond donors : 0.0
Molar Refractivity : 17.18
TPSA : 35.53 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : No
P-gp substrate : No
CYP1A2 inhibitor : No
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -6.63 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.02
Log Po/w (XLOGP3) : 0.29
Log Po/w (WLOGP) : 0.15
Log Po/w (MLOGP) : -0.83
Log Po/w (SILICOS-IT) : 1.02
Consensus Log Po/w : 0.33

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 2.0
Bioavailability Score : 0.55

Water Solubility

Log S (ESOL) : -0.57
Solubility : 23.8 mg/ml ; 0.27 mol/l
Class : Very soluble
Log S (Ali) : -0.6
Solubility : 22.2 mg/ml ; 0.252 mol/l
Class : Very soluble
Log S (SILICOS-IT) : 0.02
Solubility : 92.6 mg/ml ; 1.05 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.69

Safety of [ 96-49-1 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P260-P264-P270-P280-P301+P312+P330-P305+P351+P338-P314-P337+P313-P501 UN#:N/A
Hazard Statements:H302-H319-H373 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 96-49-1 ]

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

  • Upstream synthesis route of [ 96-49-1 ]
  • Downstream synthetic route of [ 96-49-1 ]

[ 96-49-1 ] Synthesis Path-Upstream   1~34

  • 1
  • [ 96-49-1 ]
  • [ 872-36-6 ]
Reference: [1] Chemische Berichte, 1992, vol. 125, # 2, p. 473 - 478
  • 2
  • [ 96-49-1 ]
  • [ 80-73-9 ]
Reference: [1] Patent: US5783706, 1998, A,
  • 3
  • [ 96-49-1 ]
  • [ 124-68-5 ]
  • [ 26654-39-7 ]
Reference: [1] Bioorganic and Medicinal Chemistry, 2006, vol. 14, # 7, p. 2190 - 2196
  • 4
  • [ 288-32-4 ]
  • [ 96-49-1 ]
  • [ 1615-14-1 ]
Reference: [1] Patent: US6294532, 2001, B1,
[2] Journal of Medicinal Chemistry, 1993, vol. 36, # 25, p. 4052 - 4060
[3] Journal of Heterocyclic Chemistry, 1990, vol. 27, # 2, p. 215 - 219
  • 5
  • [ 616-45-5 ]
  • [ 96-49-1 ]
  • [ 88-12-0 ]
YieldReaction ConditionsOperation in experiment
82.13% With TEMPOL; 1,8-diazabicyclo[5.4.0]undec-7-ene In 5,5-dimethyl-1,3-cyclohexadiene at 100 - 120℃; for 3.5 h; Dean-Stark To a 1 liter four necked flask with thermometer, dessicant tube, electrical stirrer, Dean Stark apparatus, is added 85,1g (1 mol) of butyrolactam, 130g (1.1 mol) of 1,3-dioxolan-2-one, 500ml of xylene , 300mg of 4-hydroxy-TEMPO as inhibitor and 6,4g of catalyst 1, 8-Diazabicyclo [5,4,0] undec-7-ene (DBU). [0065] The whole reaction mass is heated at 100°C to react during 30mn. Once the reaction of decarboxylation start, water is gradually generated and separated along with the water carrying agent. The reaction stops after temperature reach 120°C after 3h and no longer water is generated. [0066] The resulting product is further separated and the fraction at 90°C /9mmHg is collected. The product yield 82,13percent of N-ethenyl butyrolactam with a purity of 99,3percent.
Reference: [1] Patent: EP2835365, 2015, A1, . Location in patent: Paragraph 0064; 0065; 0066
  • 6
  • [ 96-49-1 ]
  • [ 66224-66-6 ]
  • [ 707-99-3 ]
YieldReaction ConditionsOperation in experiment
95% With triethylamine In acetonitrile at 125℃; for 14 h; Inert atmosphere In the 500 ml in the reaction bottle, adenine 37g (0.273 µM) suspended in acetonitrile 93 ml in, adding dioxolan 29.4g (0.334 µM), triethylamine 14.8g (0.146 µM) in N2 under protection 125 °C reaction 14h, slightly cold, pressure reducing recovery acetonitrile to obtain the solid particles, slightly cold, adds anhydrously ethanol 74 ml, heating to reflux and thermal insulation 1.5h, the ice-bath is cold to 0 °C under stirring 2h after-filtration, to obtain job filters the cake to dry 47.3g white powdery solid namely target product, yield 95percent.
93.3% With sodium hydroxide In DMF (N,N-dimethyl-formamide) for 3.33333 h; Heating / reflux Example 5
Preparation of 9-(2-Hydroxyethyl)adenine (5)
A 12 L, 3-necked round bottom flask was equipped with a mechanical stirrer, condenser, thermometer and heating mantle.
The flask was flushed with nitrogen and charged with adenine (504 g), ethylene carbonate (343 g), DMF (3.7 L) and sodium hydroxide (7.80 g).
The stirred mixture was heated to reflux (approximately 80 minutes to reach reflux, pot temperature=145° C.), and then refluxed for 2 hours.
The heating mantle was removed and the yellow solution was cooled to below 100° C.
The resulting mixture was then cooled to 5° C. in an ice bath and diluted with toluene (3.8 L).
The resulting mixture was stirred at <10° C. for 2 hours and then filtered.
The collected solid was washed with toluene (2*0.5) and cold ethanol (1.5 L), then dried to constant weight (-30 in.
Hg, 50° C., 14 h).
The solid 5 was analyzed by HPLC and 1H-NMR (DMSO-d6).
82.7% With sodium hydroxide In N,N-dimethyl-formamide for 4 h; Reflux; Large scale The mechanical stirrer, reflux condenser and thermometer were installed in a 10 L reaction flask.To this, 3 kg (22.22 mol) of adenine, 2.14 kg (24.32 mol) of ethylene carbonate, 20 g (0.5 mol) of sodium hydroxide and 7 L of DMF were added thereto in turn, followed by stirring and heating under reflux for 4 hours.The reaction was terminated, cooled to room temperature, filtered, and the filter cake was dried under vacuum at 70 ° C for 6 hours.9-hydroxyethyl adenine as an off-white solid powder 3.29kg, Mp: 225 ~ 227 (decomposition), the yield of 82.7percent.
Reference: [1] Patent: CN106699814, 2017, A, . Location in patent: Paragraph 0020-0021
[2] Molecules, 2012, vol. 17, # 11, p. 13290 - 13306
[3] Patent: US2003/225277, 2003, A1, . Location in patent: Page 10-11
[4] Tetrahedron Letters, 2006, vol. 47, # 11, p. 1767 - 1770
[5] Patent: CN104387421, 2016, B, . Location in patent: Paragraph 0026-0028
[6] Collection of Czechoslovak Chemical Communications, 1986, vol. 51, # 2, p. 459 - 477
[7] Macromolecules, 2010, vol. 43, # 3, p. 1245 - 1252
[8] Biomacromolecules, 2011, vol. 12, # 4, p. 1370 - 1379
[9] Bioorganic and Medicinal Chemistry Letters, 2000, vol. 10, # 12, p. 1347 - 1350
[10] Journal of Organic Chemistry, 1999, vol. 64, # 13, p. 4627 - 4634
[11] Bioorganic and Medicinal Chemistry, 2009, vol. 17, # 17, p. 6218 - 6232
  • 7
  • [ 96-49-1 ]
  • [ 66224-66-6 ]
  • [ 707-99-3 ]
  • [ 126595-74-2 ]
YieldReaction ConditionsOperation in experiment
77 - 97 %Chromat. With sodium hydroxide In DMF (N,N-dimethyl-formamide) at 150 - 160℃; for 3 h; Heating / reflux In general, a mixture of alkylene carbonate (11.0 mmole), the heterocyclic base (10.0 mmole) and solid [NAOH] (0.5 mmol) in a solvent (e. g., DMA) (20 ml) was heated at [150°C] for 3 h. Then, the solvent was either evaporated and the residue taken up with a wash solvent, or diluted with a first solvent to precipitate the reaction products followed by a wash step with a wash solvent or wash solvent mixture (optionally followed by crystallization [FROMAPOS;A] crystallization solvent). Analysis of the reaction products was performed using HPLC and conditions as described in Figure 4, and a typical elution profile using such HPLC conditions is shown in Figure 5. Selected results of various reaction conditions, solvents, and wash/crystallization procedures are shown in Tables 1-3. For better visualization of the numerical differences in selectivity and yield, the following grayscale of Table A was used: Total Yield (in Shade Selectivity (as percent N9 alkylated percent) product) 50-64 Less than 76 65-74 77-83 r 75-84'i'84-87 88-90 a.. 3 _ s. 96-100 97-100 96-100,,, o 97_100 Table A Interestingly, as can be seen from Table 1 of Figure 1, when the solvent for dilution and crystallization was, or contained an aprotic and [APOLAR] solvent (here: toluene), and when DMF was used as a reaction solvent (and further depending on reaction temperature and workup), either the total yield was desirable at relatively undesirable selectivity, or the selectivity was desirable at relatively undesirable total yield. Replacement of the reaction solvent DMF with alternative solvents (shown here: DEF and DMA) appeared to improve the disparity between total yield and selectivity in a relatively unpredictable manner. Moreover, where the disparity between total yield and selectivity improved, total yields and selectivities were generally lower and frequently were at undesirable levels. After numerous further modifications (date not shown), the inventors eliminated the step of dilution of the reaction solvent by evaporation to force the reaction product from the solvent, and exemplary data on total yield and selectivity are shown in Table 2 of Figure 2. These data suggested that elimination of the dilution step tended to increase the total yield to at least some degree. However, improvement of the selectivity while maintaining relatively high total yields was inconsistent. In still further experiments, the inventors replaced the non-polar solvents for [DILUTION.] of the reaction solvent with relatively high polar solvents (IPA, ethyl acetate, acetonitrile, etc. ) when DMA was used as a reaction solvent. Surprisingly, and especially where DMA was the reaction solvent and IPA was the dilution and wash solvent, consistent high yields at high selectivity could be achieved under several reaction conditions as shown in the exemplary data on total yield and selectivity in Table 3 of Figure 3. Specifically, the total yield of product was as high as [91 percent] at an N9-alkylated product content of 97percent and an N7- alkylated byproduct content of 1.34percent (with [NAOH] as catalyst and 150 centigrade reaction temperature). Similarly, the total yield of product was as high as 87percent at an N9-alkylated product content of 97percent and an N7-alkylated byproduct content of 1.15percent (with [NAOH] as catalyst and 160 centigrade reaction temperature), and the total yield of product was as high as 82percent at a N9-alkylated product content of 98percent and a N7-alkylated byproduct content of 0.96percent (with [NAOH] as catalyst and 140 centigrade reaction temperature). Moreover, by using DMA as a reaction solvent various advantages other than higher total yield and an increase of selectivity may be achieved. Among other things, the solubility of various heterocyclic bases, and especially adenine, is significantly increased as shown in Table B below. Solvent Solubility at RT Solubility at 150°C DMF 2.90 m/ml 29. 0 mg/ml DEF 1. 36 mg/ml 13. 9 mg/ml DMA 4. 00 mg/ml 37.0 mg/ml [ TABLE B] Consequently, overall consumption of solvent may be significantly reduced by virtue of the increased solubility of the heterocyclic base in DMA (at least compared to DMF as reaction solvent), which in turn reduces the cost of preparing the alkylated heterocyclic base. Still further, due to the higher boiling point of DMA as compared to DMF (166.1 Centigrade as compared to 155 Centigrade, respectively) the reaction may be performed at a temperature that is further away from the boiling point of the reaction solvent, which increases the operational safety of the reaction. Moreover, while addition of a basic catalyst is generally not required, a basic catalyst, and preferably [NAOH] will benefit the total yield and selectivity.
98 %Chromat. With sodium ethanolate In DMF (N,N-dimethyl-formamide) at 130℃; for 3 h; In general, a mixture of alkylene carbonate (11.0 mmole), the heterocyclic base (10.0 mmole) and solid [NAOH] (0.5 mmol) in a solvent (e. g., DMA) (20 ml) was heated at [150°C] for 3 h. Then, the solvent was either evaporated and the residue taken up with a wash solvent, or diluted with a first solvent to precipitate the reaction products followed by a wash step with a wash solvent or wash solvent mixture (optionally followed by crystallization [FROMAPOS;A] crystallization solvent). Analysis of the reaction products was performed using HPLC and conditions as described in Figure 4, and a typical elution profile using such HPLC conditions is shown in Figure 5. Selected results of various reaction conditions, solvents, and wash/crystallization procedures are shown in Tables 1-3. For better visualization of the numerical differences in selectivity and yield, the following grayscale of Table A was used: Total Yield (in Shade Selectivity (as percent N9 alkylated percent) product) 50-64 Less than 76 65-74 77-83 r 75-84'i'84-87 88-90 a.. 3 _ s. 96-100 97-100 96-100,,, o 97_100 Table A Interestingly, as can be seen from Table 1 of Figure 1, when the solvent for dilution and crystallization was, or contained an aprotic and [APOLAR] solvent (here: toluene), and when DMF was used as a reaction solvent (and further depending on reaction temperature and workup), either the total yield was desirable at relatively undesirable selectivity, or the selectivity was desirable at relatively undesirable total yield. Replacement of the reaction solvent DMF with alternative solvents (shown here: DEF and DMA) appeared to improve the disparity between total yield and selectivity in a relatively unpredictable manner. Moreover, where the disparity between total yield and selectivity improved, total yields and selectivities were generally lower and frequently were at undesirable levels. After numerous further modifications (date not shown), the inventors eliminated the step of dilution of the reaction solvent by evaporation to force the reaction product from the solvent, and exemplary data on total yield and selectivity are shown in Table 2 of Figure 2. These data suggested that elimination of the dilution step tended to increase the total yield to at least some degree. However, improvement of the selectivity while maintaining relatively high total yields was inconsistent. In still further experiments, the inventors replaced the non-polar solvents for [DILUTION.] of the reaction solvent with relatively high polar solvents (IPA, ethyl acetate, acetonitrile, etc. ) when DMA was used as a reaction solvent. Surprisingly, and especially where DMA was the reaction solvent and IPA was the dilution and wash solvent, consistent high yields at high selectivity could be achieved under several reaction conditions as shown in the exemplary data on total yield and selectivity in Table 3 of Figure 3. Specifically, the total yield of product was as high as [91 percent] at an N9-alkylated product content of 97percent and an N7- alkylated byproduct content of 1.34percent (with [NAOH] as catalyst and 150 centigrade reaction temperature). Similarly, the total yield of product was as high as 87percent at an N9-alkylated product content of 97percent and an N7-alkylated byproduct content of 1.15percent (with [NAOH] as catalyst and 160 centigrade reaction temperature), and the total yield of product was as high as 82percent at a N9-alkylated product content of 98percent and a N7-alkylated byproduct content of 0.96percent (with [NAOH] as catalyst and 140 centigrade reaction temperature). Moreover, by using DMA as a reaction solvent various advantages other than higher total yield and an increase of selectivity may be achieved. Among other things, the solubility of various heterocyclic bases, and especially adenine, is significantly increased as shown in Table B below. Solvent Solubility at RT Solubility at 150°C DMF 2.90 m/ml 29. 0 mg/ml DEF 1. 36 mg/ml 13. 9 mg/ml DMA 4. 00 mg/ml 37.0 mg/ml [ TABLE B] Consequently, overall consumption of solvent may be significantly reduced by virtue of the increased solubility of the heterocyclic base in DMA (at least compared to DMF as reaction solvent), which in turn reduces the cost of preparing the alkylated heterocyclic base. Still further, due to the higher boiling point of DMA as compared to DMF (166.1 Centigrade as compared to 155 Centigrade, respectively) the reaction may be performed at a temperature that is further away from the boiling point of the reaction solvent, which increases the operational safety of the reaction. Moreover, while addition of a basic catalyst is generally not required, a basic catalyst, and preferably [NAOH] will benefit the total yield and selectivity.
76 - 98 %Chromat. With sodium hydroxide In ISOPROPYLAMIDE at 140 - 160℃; for 3 h; In general, a mixture of alkylene carbonate (11.0 mmole), the heterocyclic base (10.0 mmole) and solid [NAOH] (0.5 mmol) in a solvent (e. g., DMA) (20 ml) was heated at [150°C] for 3 h. Then, the solvent was either evaporated and the residue taken up with a wash solvent, or diluted with a first solvent to precipitate the reaction products followed by a wash step with a wash solvent or wash solvent mixture (optionally followed by crystallization [FROMAPOS;A] crystallization solvent). Analysis of the reaction products was performed using HPLC and conditions as described in Figure 4, and a typical elution profile using such HPLC conditions is shown in Figure 5. Selected results of various reaction conditions, solvents, and wash/crystallization procedures are shown in Tables 1-3. For better visualization of the numerical differences in selectivity and yield, the following grayscale of Table A was used: Total Yield (in Shade Selectivity (as percent N9 alkylated percent) product) 50-64 Less than 76 65-74 77-83 r 75-84'i'84-87 88-90 a.. 3 _ s. 96-100 97-100 96-100,,, o 97_100 Table A Interestingly, as can be seen from Table 1 of Figure 1, when the solvent for dilution and crystallization was, or contained an aprotic and [APOLAR] solvent (here: toluene), and when DMF was used as a reaction solvent (and further depending on reaction temperature and workup), either the total yield was desirable at relatively undesirable selectivity, or the selectivity was desirable at relatively undesirable total yield. Replacement of the reaction solvent DMF with alternative solvents (shown here: DEF and DMA) appeared to improve the disparity between total yield and selectivity in a relatively unpredictable manner. Moreover, where the disparity between total yield and selectivity improved, total yields and selectivities were generally lower and frequently were at undesirable levels. After numerous further modifications (date not shown), the inventors eliminated the step of dilution of the reaction solvent by evaporation to force the reaction product from the solvent, and exemplary data on total yield and selectivity are shown in Table 2 of Figure 2. These data suggested that elimination of the dilution step tended to increase the total yield to at least some degree. However, improvement of the selectivity while maintaining relatively high total yields was inconsistent. In still further experiments, the inventors replaced the non-polar solvents for [DILUTION.] of the reaction solvent with relatively high polar solvents (IPA, ethyl acetate, acetonitrile, etc. ) when DMA was used as a reaction solvent. Surprisingly, and especially where DMA was the reaction solvent and IPA was the dilution and wash solvent, consistent high yields at high selectivity could be achieved under several reaction conditions as shown in the exemplary data on total yield and selectivity in Table 3 of Figure 3. Specifically, the total yield of product was as high as [91 percent] at an N9-alkylated product content of 97percent and an N7- alkylated byproduct content of 1.34percent (with [NAOH] as catalyst and 150 centigrade reaction temperature). Similarly, the total yield of product was as high as 87percent at an N9-alkylated product content of 97percent and an N7-alkylated byproduct content of 1.15percent (with [NAOH] as catalyst and 160 centigrade reaction temperature), and the total yield of product was as high as 82percent at a N9-alkylated product content of 98percent and a N7-alkylated byproduct content of 0.96percent (with [NAOH] as catalyst and 140 centigrade reaction temperature). Moreover, by using DMA as a reaction solvent various advantages other than higher total yield and an increase of selectivity may be achieved. Among other things, the solubility of various heterocyclic bases, and especially adenine, is significantly increased as shown in Table B below. Solvent Solubility at RT Solubility at 150°C DMF 2.90 m/ml 29. 0 mg/ml DEF 1. 36 mg/ml 13. 9 mg/ml DMA 4. 00 mg/ml 37.0 mg/ml [ TABLE B] Consequently, overall consumption of solvent may be significantly reduced by virtue of the increased solubility of the heterocyclic base in DMA (at least compared to DMF as reaction solvent), which in turn reduces the cost of preparing the alkylated heterocyclic base. Still further, due to the higher boiling point of DMA as compared to DMF (166.1 Centigrade as compared to 155 Centigrade, respectively) the reaction may be performed at a temperature that is further away from the boiling point of the reaction solvent, which increases the operational safety of the reaction. Moreover, while addition of a basic catalyst is generally not required, a basic catalyst, and preferably [NAOH] will benefit the total yield and selectivity.
77 %Chromat. With sodium hydroxide In N-formyldiethylamine at 150℃; for 3 h; In general, a mixture of alkylene carbonate (11.0 mmole), the heterocyclic base (10.0 mmole) and solid [NAOH] (0.5 mmol) in a solvent (e. g., DMA) (20 ml) was heated at [150°C] for 3 h. Then, the solvent was either evaporated and the residue taken up with a wash solvent, or diluted with a first solvent to precipitate the reaction products followed by a wash step with a wash solvent or wash solvent mixture (optionally followed by crystallization [FROMAPOS;A] crystallization solvent). Analysis of the reaction products was performed using HPLC and conditions as described in Figure 4, and a typical elution profile using such HPLC conditions is shown in Figure 5. Selected results of various reaction conditions, solvents, and wash/crystallization procedures are shown in Tables 1-3. For better visualization of the numerical differences in selectivity and yield, the following grayscale of Table A was used: Total Yield (in Shade Selectivity (as percent N9 alkylated percent) product) 50-64 Less than 76 65-74 77-83 r 75-84'i'84-87 88-90 a.. 3 _ s. 96-100 97-100 96-100,,, o 97_100 Table A Interestingly, as can be seen from Table 1 of Figure 1, when the solvent for dilution and crystallization was, or contained an aprotic and [APOLAR] solvent (here: toluene), and when DMF was used as a reaction solvent (and further depending on reaction temperature and workup), either the total yield was desirable at relatively undesirable selectivity, or the selectivity was desirable at relatively undesirable total yield. Replacement of the reaction solvent DMF with alternative solvents (shown here: DEF and DMA) appeared to improve the disparity between total yield and selectivity in a relatively unpredictable manner. Moreover, where the disparity between total yield and selectivity improved, total yields and selectivities were generally lower and frequently were at undesirable levels. After numerous further modifications (date not shown), the inventors eliminated the step of dilution of the reaction solvent by evaporation to force the reaction product from the solvent, and exemplary data on total yield and selectivity are shown in Table 2 of Figure 2. These data suggested that elimination of the dilution step tended to increase the total yield to at least some degree. However, improvement of the selectivity while maintaining relatively high total yields was inconsistent. In still further experiments, the inventors replaced the non-polar solvents for [DILUTION.] of the reaction solvent with relatively high polar solvents (IPA, ethyl acetate, acetonitrile, etc. ) when DMA was used as a reaction solvent. Surprisingly, and especially where DMA was the reaction solvent and IPA was the dilution and wash solvent, consistent high yields at high selectivity could be achieved under several reaction conditions as shown in the exemplary data on total yield and selectivity in Table 3 of Figure 3. Specifically, the total yield of product was as high as [91 percent] at an N9-alkylated product content of 97percent and an N7- alkylated byproduct content of 1.34percent (with [NAOH] as catalyst and 150 centigrade reaction temperature). Similarly, the total yield of product was as high as 87percent at an N9-alkylated product content of 97percent and an N7-alkylated byproduct content of 1.15percent (with [NAOH] as catalyst and 160 centigrade reaction temperature), and the total yield of product was as high as 82percent at a N9-alkylated product content of 98percent and a N7-alkylated byproduct content of 0.96percent (with [NAOH] as catalyst and 140 centigrade reaction temperature). Moreover, by using DMA as a reaction solvent various advantages other than higher total yield and an increase of selectivity may be achieved. Among other things, the solubility of various heterocyclic bases, and especially adenine, is significantly increased as shown in Table B below. Solvent Solubility at RT Solubility at 150°C DMF 2.90 m/ml 29. 0 mg/ml DEF 1. 36 mg/ml 13. 9 mg/ml DMA 4. 00 mg/ml 37.0 mg/ml [ TABLE B] Consequently, overall consumption of solvent may be significantly reduced by virtue of the increased solubility of the heterocyclic base in DMA (at least compared to DMF as reaction solvent), which in turn reduces the cost of preparing the alkylated heterocyclic base. Still further, due to the higher boiling point of DMA as compared to DMF (166.1 Centigrade as compared to 155 Centigrade, respectively) the reaction may be performed at a temperature that is further away from the boiling point of the reaction solvent, which increases the operational safety of the reaction. Moreover, while addition of a basic catalyst is generally not required, a basic catalyst, and preferably [NAOH] will benefit the total yield and selectivity.
55 - 83 %Chromat. at 150 - 160℃; for 3 h; In general, a mixture of alkylene carbonate (11.0 mmole), the heterocyclic base (10.0 mmole) and solid [NAOH] (0.5 mmol) in a solvent (e. g., DMA) (20 ml) was heated at [150°C] for 3 h. Then, the solvent was either evaporated and the residue taken up with a wash solvent, or diluted with a first solvent to precipitate the reaction products followed by a wash step with a wash solvent or wash solvent mixture (optionally followed by crystallization [FROMAPOS;A] crystallization solvent). Analysis of the reaction products was performed using HPLC and conditions as described in Figure 4, and a typical elution profile using such HPLC conditions is shown in Figure 5. Selected results of various reaction conditions, solvents, and wash/crystallization procedures are shown in Tables 1-3. For better visualization of the numerical differences in selectivity and yield, the following grayscale of Table A was used: Total Yield (in Shade Selectivity (as percent N9 alkylated percent) product) 50-64 Less than 76 65-74 77-83 r 75-84'i'84-87 88-90 a.. 3 _ s. 96-100 97-100 96-100,,, o 97_100 Table A Interestingly, as can be seen from Table 1 of Figure 1, when the solvent for dilution and crystallization was, or contained an aprotic and [APOLAR] solvent (here: toluene), and when DMF was used as a reaction solvent (and further depending on reaction temperature and workup), either the total yield was desirable at relatively undesirable selectivity, or the selectivity was desirable at relatively undesirable total yield. Replacement of the reaction solvent DMF with alternative solvents (shown here: DEF and DMA) appeared to improve the disparity between total yield and selectivity in a relatively unpredictable manner. Moreover, where the disparity between total yield and selectivity improved, total yields and selectivities were generally lower and frequently were at undesirable levels. After numerous further modifications (date not shown), the inventors eliminated the step of dilution of the reaction solvent by evaporation to force the reaction product from the solvent, and exemplary data on total yield and selectivity are shown in Table 2 of Figure 2. These data suggested that elimination of the dilution step tended to increase the total yield to at least some degree. However, improvement of the selectivity while maintaining relatively high total yields was inconsistent. In still further experiments, the inventors replaced the non-polar solvents for [DILUTION.] of the reaction solvent with relatively high polar solvents (IPA, ethyl acetate, acetonitrile, etc. ) when DMA was used as a reaction solvent. Surprisingly, and especially where DMA was the reaction solvent and IPA was the dilution and wash solvent, consistent high yields at high selectivity could be achieved under several reaction conditions as shown in the exemplary data on total yield and selectivity in Table 3 of Figure 3. Specifically, the total yield of product was as high as [91 percent] at an N9-alkylated product content of 97percent and an N7- alkylated byproduct content of 1.34percent (with [NAOH] as catalyst and 150 centigrade reaction temperature). Similarly, the total yield of product was as high as 87percent at an N9-alkylated product content of 97percent and an N7-alkylated byproduct content of 1.15percent (with [NAOH] as catalyst and 160 centigrade reaction temperature), and the total yield of product was as high as 82percent at a N9-alkylated product content of 98percent and a N7-alkylated byproduct content of 0.96percent (with [NAOH] as catalyst and 140 centigrade reaction temperature). Moreover, by using DMA as a reaction solvent various advantages other than higher total yield and an increase of selectivity may be achieved. Among other things, the solubility of various heterocyclic bases, and especially adenine, is significantly increased as shown in Table B below. Solvent Solubility at RT Solubility at 150°C DMF 2.90 m/ml 29. 0 mg/ml DEF 1. 36 mg/ml 13. 9 mg/ml DMA 4. 00 mg/ml 37.0 mg/ml [ TABLE B] Consequently, overall consumption of solvent may be significantly reduced by virtue of the increased solubility of the heterocyclic base in DMA (at least compared to DMF as reaction solvent), which in turn reduces the cost of preparing the alkylated heterocyclic base. Still further, due to the higher boiling point of DMA as compared to DMF (166.1 Centigrade as compared to 155 Centigrade, respectively) the reaction may be performed at a temperature that is further away from the boiling point of the reaction solvent, which increases the operational safety of the reaction. Moreover, while addition of a basic catalyst is generally not required, a basic catalyst, and preferably [NAOH] will benefit the total yield and selectivity.
73 %Chromat. at 150℃; for 3 h; In general, a mixture of alkylene carbonate (11.0 mmole), the heterocyclic base (10.0 mmole) and solid [NAOH] (0.5 mmol) in a solvent (e. g., DMA) (20 ml) was heated at [150°C] for 3 h. Then, the solvent was either evaporated and the residue taken up with a wash solvent, or diluted with a first solvent to precipitate the reaction products followed by a wash step with a wash solvent or wash solvent mixture (optionally followed by crystallization [FROMAPOS;A] crystallization solvent). Analysis of the reaction products was performed using HPLC and conditions as described in Figure 4, and a typical elution profile using such HPLC conditions is shown in Figure 5. Selected results of various reaction conditions, solvents, and wash/crystallization procedures are shown in Tables 1-3. For better visualization of the numerical differences in selectivity and yield, the following grayscale of Table A was used: Total Yield (in Shade Selectivity (as percent N9 alkylated percent) product) 50-64 Less than 76 65-74 77-83 r 75-84'i'84-87 88-90 a.. 3 _ s. 96-100 97-100 96-100,,, o 97_100 Table A Interestingly, as can be seen from Table 1 of Figure 1, when the solvent for dilution and crystallization was, or contained an aprotic and [APOLAR] solvent (here: toluene), and when DMF was used as a reaction solvent (and further depending on reaction temperature and workup), either the total yield was desirable at relatively undesirable selectivity, or the selectivity was desirable at relatively undesirable total yield. Replacement of the reaction solvent DMF with alternative solvents (shown here: DEF and DMA) appeared to improve the disparity between total yield and selectivity in a relatively unpredictable manner. Moreover, where the disparity between total yield and selectivity improved, total yields and selectivities were generally lower and frequently were at undesirable levels. After numerous further modifications (date not shown), the inventors eliminated the step of dilution of the reaction solvent by evaporation to force the reaction product from the solvent, and exemplary data on total yield and selectivity are shown in Table 2 of Figure 2. These data suggested that elimination of the dilution step tended to increase the total yield to at least some degree. However, improvement of the selectivity while maintaining relatively high total yields was inconsistent. In still further experiments, the inventors replaced the non-polar solvents for [DILUTION.] of the reaction solvent with relatively high polar solvents (IPA, ethyl acetate, acetonitrile, etc. ) when DMA was used as a reaction solvent. Surprisingly, and especially where DMA was the reaction solvent and IPA was the dilution and wash solvent, consistent high yields at high selectivity could be achieved under several reaction conditions as shown in the exemplary data on total yield and selectivity in Table 3 of Figure 3. Specifically, the total yield of product was as high as [91 percent] at an N9-alkylated product content of 97percent and an N7- alkylated byproduct content of 1.34percent (with [NAOH] as catalyst and 150 centigrade reaction temperature). Similarly, the total yield of product was as high as 87percent at an N9-alkylated product content of 97percent and an N7-alkylated byproduct content of 1.15percent (with [NAOH] as catalyst and 160 centigrade reaction temperature), and the total yield of product was as high as 82percent at a N9-alkylated product content of 98percent and a N7-alkylated byproduct content of 0.96percent (with [NAOH] as catalyst and 140 centigrade reaction temperature). Moreover, by using DMA as a reaction solvent various advantages other than higher total yield and an increase of selectivity may be achieved. Among other things, the solubility of various heterocyclic bases, and especially adenine, is significantly increased as shown in Table B below. Solvent Solubility at RT Solubility at 150°C DMF 2.90 m/ml 29. 0 mg/ml DEF 1. 36 mg/ml 13. 9 mg/ml DMA 4. 00 mg/ml 37.0 mg/ml [ TABLE B] Consequently, overall consumption of solvent may be significantly reduced by virtue of the increased solubility of the heterocyclic base in DMA (at least compared to DMF as reaction solvent), which in turn reduces the cost of preparing the alkylated heterocyclic base. Still further, due to the higher boiling point of DMA as compared to DMF (166.1 Centigrade as compared to 155 Centigrade, respectively) the reaction may be performed at a temperature that is further away from the boiling point of the reaction solvent, which increases the operational safety of the reaction. Moreover, while addition of a basic catalyst is generally not required, a basic catalyst, and preferably [NAOH] will benefit the total yield and selectivity.

Reference: [1] Patent: WO2004/14912, 2004, A1, . Location in patent: Page 10-13
[2] Patent: WO2004/14912, 2004, A1, . Location in patent: Page 10-13
[3] Patent: WO2004/14912, 2004, A1, . Location in patent: Page 10-13
[4] Patent: WO2004/14912, 2004, A1, . Location in patent: Page 10-13
[5] Patent: WO2004/14912, 2004, A1, . Location in patent: Page 10-13
[6] Patent: WO2004/14912, 2004, A1, . Location in patent: Page 10-13
  • 8
  • [ 96-49-1 ]
  • [ 15571-48-9 ]
  • [ 66224-66-6 ]
  • [ 707-99-3 ]
YieldReaction ConditionsOperation in experiment
90% With sodium hydroxide In N,N-dimethyl-formamide; toluene EXAMPLE 1a
Adenine to PMEA using Magnesium Isopropoxide. To a suspension of adenine (16.8 g, 0.124 mol) in DMF (41.9 ml) was added ethylene carbonate (12.1 g, 0.137 mol) and sodium hydroxide (0.100 g, 0.0025 mol).
The mixture was heated at 130° C. overnight.
The reaction was cooled to below 50° C. and toluene (62.1 ml) was added.
The slurry was further cooled to 5° C. for 2 hours, filtered, and rinsed with toluene (2*).
The wet solid was dried in vacuo at 65° C. to yield 20.0 g (90percent) of 9-(2hydroxyethyl)adenine as an off-white solid. Mp: 238-240° C.
Reference: [1] Patent: US2004/18150, 2004, A1,
  • 9
  • [ 96-49-1 ]
  • [ 66-22-8 ]
  • [ 936-70-9 ]
Reference: [1] Patent: US6335432, 2002, B1, . Location in patent: Example 5
[2] Journal of Organic Chemistry, 1997, vol. 62, # 1, p. 88 - 92
[3] Nucleosides, Nucleotides and Nucleic Acids, 2003, vol. 22, # 5-8, p. 743 - 745
[4] Tetrahedron Letters, 2006, vol. 47, # 11, p. 1767 - 1770
[5] Chemistry - An Asian Journal, 2016, vol. 11, # 1, p. 112 - 119
  • 10
  • [ 96-49-1 ]
  • [ 66-22-8 ]
  • [ 936-70-9 ]
  • [ 711-66-0 ]
Reference: [1] Chemistry - A European Journal, 2007, vol. 13, # 30, p. 8411 - 8427
  • 11
  • [ 15022-08-9 ]
  • [ 107-21-1 ]
  • [ 96-49-1 ]
  • [ 111-45-5 ]
Reference: [1] Chemistry - A European Journal, 2012, vol. 18, # 9, p. 2660 - 2665
  • 12
  • [ 96-49-1 ]
  • [ 111-27-3 ]
  • [ 7523-15-1 ]
YieldReaction ConditionsOperation in experiment
68 mol at 80℃; for 4 h; Autoclave General procedure: EC (10 mmol), alcohol (100 mmol), and catalyst (5 wtpercent of EC) were taken in a Teflon-lined stainless-steel autoclave placed in a rotating hydrothermal reactor (Hiro Co., Japan; rotation speed = 50 rpm). Reactions were conducted at 40–100°C for 0.5–6 h. After completion of the reaction, the autoclave was cooled to 25°C, and the catalyst was separated by centrifugation/filtration. The liquid product was analyzed and quantified by gas chromatography (GC, Varian 3800; CP-SIL 5 column; 50 m × 0.25 mm × 0.25 m). The influence of reaction parameters (reaction time, reaction temperature, catalyst amount, and type of alcohol) on product yield was investigated. For comparison, experiments were also conducted with PC instead of EC. Those runs were carried out at 80–170°C.
Reference: [1] Journal of Molecular Catalysis A: Chemical, 2015, vol. 398, p. 42 - 49
  • 13
  • [ 96-49-1 ]
  • [ 4151-50-2 ]
  • [ 1691-99-2 ]
Reference: [1] Justus Liebigs Annalen der Chemie, 1973, p. 11 - 19
  • 14
  • [ 96-49-1 ]
  • [ 140-29-4 ]
  • [ 935-44-4 ]
Reference: [1] Tetrahedron Letters, 2005, vol. 46, # 42, p. 7247 - 7248
  • 15
  • [ 96-49-1 ]
  • [ 106-44-5 ]
  • [ 15149-10-7 ]
Reference: [1] Bulletin of the Chemical Society of Japan, 1973, vol. 46, # 2, p. 553 - 556
  • 16
  • [ 96-49-1 ]
  • [ 106-49-0 ]
  • [ 2933-74-6 ]
  • [ 3077-12-1 ]
Reference: [1] Synlett, 2006, # 9, p. 1374 - 1378
[2] Organic and Biomolecular Chemistry, 2010, vol. 8, # 22, p. 5187 - 5198
  • 17
  • [ 96-49-1 ]
  • [ 75-44-5 ]
  • [ 106-48-9 ]
  • [ 13001-28-0 ]
YieldReaction ConditionsOperation in experiment
93% With sodium hydroxide; tributyl-amine In <i>N</i>-methyl-acetamide; water EXAMPLE P1
4-Chloro-(2-chloroethoxy)-benzene
26.4 g of 4-chlorophenol and 18.7 g of ethylene carbonate are heated slowly to +150° C. after addition of 1 g of tributylamine.
The reaction mixture is kept at +150° C. during approximately 3 hours until the evolution of carbon dioxide gas ceased.
The reaction mixture then is cooled to +85° C. and 1 g of dimethylformamide is added.
Subsequently 24 g of phosgene are bubbled through the mixture.
The reaction temperature is kept at +85° C. for eight hours and then lowered to +60° C. 100 ml of water are added to destroy an excess of phosgene and subsequently the mixture is neutralized with 10.5 g of a 25percent aqueous solution of sodium hydroxide.
The organic layer is separated and distilled at 150°-152° C./40 mb to give 36.0 g (93percent yield) of 4-chloro-(2-chloroethoxy)-benzene.
93% With sodium hydroxide; tributyl-amine In <i>N</i>-methyl-acetamide; water Example P1
4-Chloro-(2-chloroethoxy)-benzene
26.4 g of 4-chlorophenol and 18.7 g of ethylene carbonate are heated slowly to +150° C. after addition of 1 g of tributylamine.
The reaction mixture is kept at +150° C. during approximately 3 hours until the evolution of carbon dioxide gas ceased.
The reaction mixture then is cooled to +85° C. and 1 g of dimethylformamide is added.
Subsequently 24 g of phosgene are bubbled through the mixture.
The reaction temperature is kept at +85° C. for eight hours and then lowered to +60° C. 100 ml of water are added to destroy an excess of phosgene and subsequently the mixture is neutralized with 10.5 g of a 25percent aqueous solution of sodium hydroxide.
The organic layer is separated and distillated at 150°-152° C./40 mb to give 36.0 g (93percent yield) of 4-chloro-(2-chloroethoxy)-benzene.
Reference: [1] Patent: US4959501, 1990, A,
[2] Patent: US4806528, 1989, A,
  • 18
  • [ 96-49-1 ]
  • [ 1892-43-9 ]
  • [ 106-48-9 ]
  • [ 13001-28-0 ]
Reference: [1] Patent: US4959501, 1990, A,
  • 19
  • [ 96-49-1 ]
  • [ 98-64-6 ]
  • [ 94-20-2 ]
Reference: [1] Patent: US4062889, 1977, A,
  • 20
  • [ 96-49-1 ]
  • [ 103-49-1 ]
  • [ 101-06-4 ]
YieldReaction ConditionsOperation in experiment
83% at 20 - 140℃; for 26 h; Preparation Example: Preparation Acetic acid 2-dibenzylamino-ethyl ester; Stepi : 0.5 gram of dibenzylamine (2.5 mmol), 0.446 gram of ethylenecarbonate (5 mmol) and 0.215 gram of tetraethylammoniumiodide (083 mmol) were mixed together at room temperature. The solid mixture was then heated at 1409C and the resulting suspension was stirred at this temperature for 26 hours. The reaction mixture was diluted with ethyl acetate and extracted with 1 OmL of a 0.5M solution of sodium hydroxide. The aqueous phase was washed with ethyl acetate and the combined organic phases were washed twice with brine. The organic phase was dried on magnesium sulfate, filtered, concentrated under reduced pressure and purified by flash chromatography on silica gel (eluant: ethylacetate/hexane 1/2) to afford 0.5 gram of N, N- dibenzyl-2-aminoethanol (yield: 83percent) as an oil.
Reference: [1] Patent: WO2008/62006, 2008, A1, . Location in patent: Page/Page column 13
  • 21
  • [ 96-49-1 ]
  • [ 94-71-3 ]
  • [ 3250-73-5 ]
YieldReaction ConditionsOperation in experiment
100% With potassium carbonate In toluene at 115℃; for 24 h; 2-ethoxyphenols (55.0g, 0.398mol), ethylenecarbonates (70.1g, 0.796mol), andpotassium carbonates (12.1g, 0.088mol) were put into the toluene (550ml) and itmixed reflux in 24 hours 115. After the ethyl acetate (275ml) and saltywater (550ml) were added to the reactant and the organic layer was extractedand the anhydrous sodium sulfate was added to the organic layer and it dried itfiltered and it was the filtrate concentrated under reduced pressure and 2 -(2- ethoxyphenoxy) ethanol was obtained (72.5g, and the yield 100percent).
Reference: [1] Patent: KR101525493, 2015, B1, . Location in patent: Paragraph 0072; 0106-0107
  • 22
  • [ 96-49-1 ]
  • [ 1137-42-4 ]
  • [ 14814-17-6 ]
YieldReaction ConditionsOperation in experiment
95% With sodium iodide In toluene at 60℃; for 1.5 h; Reflux 4-hydroxybenzophenone (262 g, 1.32 mol)NaI (6.5 g, 0.043 mol),Ethylene carbonate (125 g, 1.42 mol) andToluene (10 mL) were added to a 2000 mL three-necked flask,Raise the temperature until the system is clear.Continue to raise the temperature to the reaction system was refluxed for 1.5h,After the TLC test reaction is completed, the heating is stopped,Cooled to 60 ° C.To the reaction system was added water and ethyl acetate,extraction,The organic phase was dried over anhydrous sodium sulfate,Concentrated to give 304 g of a pale yellow solid,Yield 95percent.
94% With sodium iodide In toluene at 99 - 176℃; for 0.5 h; A mixture of ethylene carbonate (124.6 g; 1.07 eq.), sodium iodide (6.3 g; 0.03 eq.), 4-hydroxybenzophenone (262 g; 1 eq.) and toluene (8.1 g) was heated. At99°C a clear solution was obtained. The reaction mixture was heated with reflux condenser to 176°C over one hour, during which gas evolution occurred. After an additional 1/2 hour at 176°C, the reaction mixture was cooled to 122°C and toluene (350 g) and water (24 g) was added. The lower phase was cut and discarded. More water (14 g) was added and the lower phase was again cut and discarded. Water and toluene (95 g in total) was azeotropically removed, reaching a boiling point of 11 1 °C. More toluene (1 14 g) was added and the product was isolated by filtration at 8°C. In total, 302 g of 4-(2-hydroxyethoxy)benzophenone (94percent) was obtained after drying as white crystals (99.8 percent chromatographic purity).
Reference: [1] Patent: CN104788300, 2017, B, . Location in patent: Paragraph 0038; 0039; 0040;
[2] Patent: WO2011/89385, 2011, A1, . Location in patent: Page/Page column 23
[3] Patent: US4625048, 1986, A,
  • 23
  • [ 96-49-1 ]
  • [ 120-72-9 ]
  • [ 101221-54-9 ]
  • [ 121459-15-2 ]
Reference: [1] Chinese Journal of Catalysis, 2013, vol. 34, # 6, p. 1187 - 1191
  • 24
  • [ 96-49-1 ]
  • [ 3236-71-3 ]
  • [ 117344-32-8 ]
YieldReaction ConditionsOperation in experiment
75% With potassium fluoride In N,N-dimethyl-formamide for 4 h; Inert atmosphere; Reflux 100 g (285.3 mmol) of bis (4-hydroxyphenyl) fluorene (1-1) obtained in the step 1 of Example 1, 500 ml of DMF, 52.7 g (599.0 mmol) of ethylene carbonate, 1 g of KF was added and the mixture was subjected to a reflux reaction for 4 hours. After completion of the reaction, the reaction mixture was cooled to room temperature and 1 L of purified water was added thereto, followed by stirring for 20 minutes. After 1 L of methylene chloride was added, the mixture was stirred for 30 minutes, and the organic layer was separated.(Yield: 75percent),
75% With potassium fluoride In N,N-dimethyl-formamide for 4 h; Inert atmosphere; Reflux Under a nitrogen atmosphere, 100.0 g (285.3 mmol) of bis (4-hydroxyphenyl) fluorene (4-1) obtained in the step 1 of Example 4,DMF (500 ml), ethylene carbonate52.7 g (599.0 mmol),KF 1gAnd the mixture was refluxed for 4 hours.After completion of the reaction, the reaction mixture was cooled to room temperature and 1 L of purified water was added thereto, followed by stirring for 20 minutes. After 1 L of methylene chloride was added, the mixture was stirred for 30 minutes, and the organic layer was separated. Washed with 1 L of purified water four times, and the organic layer was concentrated to obtain the target [yield 75
Reference: [1] Patent: KR101692343, 2017, B1, . Location in patent: Paragraph 0095; 0096; 0097; 0098
[2] Patent: KR101716647, 2017, B1, . Location in patent: Paragraph 0114-0117
  • 25
  • [ 96-49-1 ]
  • [ 114435-02-8 ]
YieldReaction ConditionsOperation in experiment
98.2% at 120℃; for 0.5 h; Sealed tube Into a sealed reactor, 100 g of ethylene carbonate and 370 g of N-fluorobistrifluoromethanesulfonamide were added and stirred, and the temperature was raised to 120°C. HPLC analysis until the reaction time of ethylene carbonate was undetectable , the reaction time was 0.9 h, and the reaction was stopped. The fluoroethylene carbonate product was separated by distillation and had a purity of >99.9percent and a yield of 97.8percent.the chroma was 8 Hazen. Replace the above fluorinated reagent with 390 g of N-fluorobisbenzenesulfonamide. Under the same conditions, the complete reaction time was 1/2 h, the purity was >99.9percent, the yield was 98.2percent, and the chroma was 8 Hazen.
Reference: [1] Patent: CN108033943, 2018, A, . Location in patent: Paragraph 0020; 0024; 0025
[2] Journal of Fluorine Chemistry, 2003, vol. 120, # 2, p. 105 - 110
[3] Tetrahedron Letters, 2002, vol. 43, # 8, p. 1503 - 1505
[4] Patent: WO2004/76439, 2004, A1, . Location in patent: Page/Page column 3; 4
[5] Patent: EP2196464, 2010, A1, . Location in patent: Page/Page column 4
[6] Patent: CN104072473, 2016, B, . Location in patent: Paragraph 0036-0041
[7] Patent: CN108191811, 2018, A, . Location in patent: Paragraph 0021-0023; 0025; 0027-0029
  • 26
  • [ 96-49-1 ]
  • [ 114435-02-8 ]
YieldReaction ConditionsOperation in experiment
78.4% at 45 - 55℃; Example 1 In order to charge EC in a reactor 1, EC (m.p. 36-37), which is a colorless and odorless crystal at room temperature, must be melted into a transferable solution. 10.6 kg (120.37 mol) of EC solution were charged in a reaction compartment 8 while warm water was supplied to an external cooling water jacket of the reaction compartment 8 so as to maintain the reaction compartment 8 at 45-50. While warm water was supplied to the cooling water jacket so as to maintain the temperature of the reactor at 45-50, F2 gas generated from an F2 electrolytic bath was fed into a mixer (not shown) and then mixed with N2 gas to produce 20 v/v percent F2/N2 (F2 content was 20 v percent) mixture gas. F2/N2 mixture gas was fed through an F2/N2 mixture gas inlet 2 at a lower part of the reactor into the reactor at a flow rate of 1960 l/h. Additionally, F2/N2 mixture gas was fed through a gas bubble regulating column 3 into the reactor. Packings were packed in the gas bubble regulating column. In the present example, twelve hundred raschig rings were packed in the gas bubble regulating column. The four cylindrical gas bubble regulating columns 3 were provided, and each had an internal diameter of 2, a length of 600 mm, and an internal volume of 1373 cm3. When F2/N2 mixture gas passed through a raschig ring bed, which consisted of raschig rings irregularly packed in the column, the gas flowed through various flow paths and was uniformly dispersed. At this stage, if the flow rate of the mixture gas is regulated, it is possible to make the sizes of bubbles of F2/N2 mixture gas, which is formed in the EC liquid, fine using several gas bubble regulating columns. The sizes of the bubbles depend on the number of gas bubble regulating columns, the amount of packings, and the flow rate of F2/N2 mixture gas. The use of the gas bubble regulating column contributes to formation of the fine bubbles of F2/N2 mixture gas to be reacted with EC, and to uniform dispersion of the bubbles of F2/N2 mixture gas in EC liquid. The flow rate of mixture gas was controlled by a flow controller. When F2/N2 mixture gas was fed into the reactor and a reaction started to be conducted, the reaction was intensely conducted and high reaction heat was generated. Accordingly, cooling water was supplied to the cooling water jacket and a reaction temperature was maintained at 55+/-3. The arrows in the reactor shown in FIG. 1 denote the flow direction of EC. Brine at -15 was fed into a heat exchanger at an upper part of the reactor so as to maintain a temperature of a lower part of the heat exchanger at 27+/-2. A solenoid valve was provided at a pipe for discharging unreacted gases therethrough into an absorber and a device for controlling fine pressure was connected thereto so as to control the pressure in the reactor. The pressure was controlled to 1000+30 mmAq. When the flow rate of F2 gas was 1.2 mol based on EC charged in the reactor at an initial stage, the reaction was finished. After the end of the reaction, remaining gas was removed from the reactor using 500 L/hr N2 for 30 min. The reaction results were that the total amount of product was 13.14 kg, HF was 11.63 wt percent (1.05 kg), FEC was 75.37 wt percent (8.75 kg, 82.5 mol), and DFEC was 3.0 wt percent (0.35 kg, 2.85 mol). A mole number of reacted F2 was 88.2 mol, conversion efficiency of F2 was 61.1percent, and selectivity of FEC was 93.5percent. Yield of FEC was 57.1percent based on F2.; Example 2 The reaction was conducted under the same conditions as example 1 with the exception of the following conditions. Two reactors having the same shape were employed while being serially connected. 10.6 kg of EC solution were charged in a first reactor as a main reactor and in a second reactor, and 20 v/v percent F2/N2 mixture gas as reactant gas was fed into the first reactor to conduct a first reaction. Unreacted gases, which were generated in the first reaction, were fed into the second reactor so as to be reused. The other reaction conditions were the same as example 1. As a result, the total amount of product was 25.3 kg, HF was 9.96 wt percent (2.52 kg), FEC was 52.74 wt percent (12.01 kg, 113.2 mol), and DFEC was 2.06 wt percent (0.47 kg, 3.73 mol). A mol number of reacted F2 was 116.9 mol, which meant that conversion efficiency of F2 was 80.93percent, and selectivity of FEC was 96.8percent. Yield of FEC was 78.4percent based on F2.; Example 3 The reaction was conducted under the same conditions as example 2 with the exception of the following conditions. 10.6 kg of EC solution were charged in a first reactor as a main reactor, and 10.6 kg of EC/FEC solution, which contains 35 wt percent (34.8 mol) FEC, were charged in a second reactor. 20 v/v percent F2/N2 mixture gas as reactant gas was fed into the first reactor to conduct a first reaction. Unreacted gases, which were generated in the first reaction, were fed into the second reactor so as to be reused. The other reaction conditions were the same as example 2. As a result, the total amount of product was 25.01 kg, HF was 11.79 wt percent (2.95 kg), FEC was 73.65 wt percent (16.24 kg, 153.1 mol), and DFEC was 2.99 wt percent (0.66 kg, 5.32 mol). A mol number of reacted F2 was 124.8 mol, which meant that conversion efficiency of F2 was 86.4percent, and selectivity of FEC was 94.8percent. Yield of FEC was 81.9percent based on F2. Example 1 employed one reactor 1, but examples 2 and 3 employed two reactors 1 which were serially connected to each other. When two reactors were used, unreacted F2 gas, discharged from the first reactor, was recovered, provided to form F2/N2 mixture gas, and fed into the second reactor in the same manner as the first reactor. Compared to the use of one reactor, the use of two reactors is more effective to reduce the loss of F2 gas and to increase the amount of FEC produced.
Reference: [1] Patent: US2006/167279, 2006, A1, . Location in patent: Page/Page column 3-5
[2] Patent: WO2011/36283, 2011, A2, . Location in patent: Page/Page column 11-13
  • 27
  • [ 96-49-1 ]
  • [ 857463-44-6 ]
  • [ 114435-02-8 ]
Reference: [1] Patent: WO2011/36283, 2011, A2, . Location in patent: Page/Page column 11-13
  • 28
  • [ 96-49-1 ]
  • [ 114435-02-8 ]
Reference: [1] Patent: WO2011/36281, 2011, A1, . Location in patent: Page/Page column 10-11
  • 29
  • [ 96-49-1 ]
  • [ 2075-45-8 ]
  • [ 214614-81-0 ]
YieldReaction ConditionsOperation in experiment
34%
Stage #1: With sodium hydride In N,N-dimethyl-formamide at 20℃; for 0.5 h;
Stage #2: at 20℃;
General Procedure 77
To a stirred solution of 4-bromo-1H-pyrazole in DMF was added sodium hydride at room temperature.
The mixture was stirred for 30 minutes, [1,3]dioxolan-2-one was added, the mixture was stirred and slowly warmed to room temperature.
The reaction was monitored by TLC.
After the reaction was done, EtOAc was added, washed with saturated NaHCO3, water and brine, dried with Na2SO4, filtered and concentrated.
The residue was purified by silica gel, eluants EtOAc and DCM 10percent, to give 2-(4-Bromo-pyrazol-1-yl)-ethanol 0.22 g, yield 34percent. 1H NMR (400 MHz, chloroform-D) δ ppm 7.49 (s, 1H) 7.46 (s, 1H) 4.18-4.23 (m, 2H) 3.93-3.98 (m, 2H) 3.09 (s, 1H).
34%
Stage #1: With sodium hydride In N,N-dimethyl-formamide at 20℃; for 0.5 h;
Stage #2: at 20℃;
To a stirred solution of 4-bromo-1 H-pyrazole in DMF was added sodium hydride at room temperature. The mixture was stirred for 30 minutes, [1,3]dioxolan-2-one was added, the mixture was stirred and slowly warmed to room temperature. The reaction was monitored by TLC. After the reaction was done, EtOAc was added, washed with saturated NaHCO3, water and brine, dried with Na2SO4, filtered and concentrated. The residue was purified by silica gel, eluants EtOAc and DCM 10percent, to give 2-(4-Bromo-pyrazol-1-yl)-ethanol 0.22 g, yield 34percent. 1H NMR (400 MHz, chloroform-D) 6 ppm 7.49 (s, 1 H) 7.46 (s, 1 H) 4.18 - 4.23 (m, 2 H) 3.93 - 3.98 (m, 2 H) 3.09 (s, 1 H).
Reference: [1] Patent: US2006/46991, 2006, A1, . Location in patent: Page/Page column 71
[2] Patent: WO2006/21881, 2006, A2, . Location in patent: Page/Page column 84
  • 30
  • [ 96-49-1 ]
  • [ 269410-08-4 ]
  • [ 1040377-08-9 ]
YieldReaction ConditionsOperation in experiment
91% With sodium hydroxide In N,N-dimethyl-formamide at 140℃; for 16 h; Intermediate 1182-[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxa H-pyrazol-1 -yl]ethanolA solution of 1 ,3-dioxolan-2-one (2.496 g, 28.3 mmol), 4-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)-1 H-pyrazole (5 g, 25.8 mmol) and sodium hydroxide (0.103 g, 2.58 mmol) in N,N-Dimethylformamide (DMF) (18 mL) was stirred at 140°C for 16 h. then cooled to room temperature and treated with activated charcoal (200mg). The resulting mixture was stirred at room temperature for 1 h then filtered through celite (10 g). The insoluble were washed with EtOAc (50 mL) and EtOH (50ml_). The combined filtrate and washings were concentrated in vacuo. Purification of the residue by flash chromatography on silica gel using a 50 G silica cartyridge (gradient: 0 to 40percent MeOH in DCM) gave a residue which was further purified by SP4 using a 100 G silica cartridge (eluant: 0 to 20percent MeOH in DCM) to give 2-[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazol-1 - yl]ethanol (5.58 g, 23.44 mmol, 91 percent yield) as a colourless oil which was used in the next step without further purification.LCMS (method A): Retention time 0.68 min, [M+H]+ = 239.13
85% With sodium hydroxide In N,N-dimethyl-formamide for 2.5 h; Heating / reflux INTERMEDIATE 34; 2-[4-f4.4.5.5-Tetramethyl-ri.3.21dioxaborolan-2-ylVρyrazol-l-yl1-ethanol; 4-Pyrazoleboronic acid pinacol ester (0.25 g, 1.29 mmol), ethylene carbonate(0.125 g, 1.42 mmol) and sodium hydroxide (5 mg, 0.13 mmol) were dissolved in DMF (1 mL) and the reaction mixture was heated to reflux for 2 Vi h. It was cooled to r.t. before addition of activated charcoal (25 mg). The resulting suspension was stirred at r.t. for Ih and then filtered through celite, washed with DMF (6 mL) and concentrated in vacuo to give the title compound (0.26g, 85percent) as a yellow oil. LCMS (ES+) 239.18 (M+H)+.
76% With caesium carbonate In N,N-dimethyl-formamide at 140℃; for 0.5 h; 100 mg of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole and 91 mg of 1,3-dioxolan-2-one weredissloved in 2 ml of dimethylformamide. 336 mg of cesium carbonate was heated to 140 °C, stirred for 0.5 h and thencooled to room temperature and concentrated. The residue was purified by column chromatography (ethyl acetate:petroleum ether = 30: 70) to give 93 mg of 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethanol aspale yellow oil. Yield: 76percent.1H NMR (300 MHz, DMSO-d6) δ (ppm): 1.25 (s, 12H), 3.71 (q, J= 5.4 Hz, 2H), 4.15 (t, J = 5.4 Hz, 2H), 4.87 (t, J = 5.4Hz, 1H), 7.57 (s, 1H), 7.88 (s, 1H).
7.53 g With sodium hydroxide In N,N-dimethyl-formamide at 140℃; A solution of I ,3-dioxolan-2-one (1 .902 mL, 28.5 mmol), 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)-IH-pyrazole (5.0239 g, 25.9 mmol) and sodium hydroxide (0.0998 g, 2.495 mmol) in N,Ndimethylformamide (DMF) (20 mL) was heated to 140 °C overnight. The mixture was cooled down to rt and then activated charcoal (200 mg) was added and this was stirred for 4 h before filtering through celite cartridge (10 g). The mixture was washed with EtOAc (50 mL) and EtCH (50 mL andthe combined filtrate was concentrated in vacuo to afford 7.53 g of brown oil. This was used crude in further reactions. LCMS: Not recorded.

Reference: [1] Patent: WO2011/54841, 2011, A1, . Location in patent: Page/Page column 107
[2] Patent: WO2008/44022, 2008, A1, . Location in patent: Page/Page column 35
[3] Patent: EP3112351, 2017, A1, . Location in patent: Paragraph 0041
[4] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 9, p. 3208 - 3212
[5] Patent: WO2010/19899, 2010, A1, . Location in patent: Page/Page column 155
[6] Patent: US2010/144783, 2010, A1, . Location in patent: Page/Page column 15
[7] Patent: US2011/281842, 2011, A1, . Location in patent: Page/Page column 45
[8] Patent: US2011/281868, 2011, A1, . Location in patent: Page/Page column 21
[9] Patent: US2012/208798, 2012, A1, . Location in patent: Page/Page column 48
[10] Patent: WO2014/140076, 2014, A1, . Location in patent: Page/Page column 208
  • 31
  • [ 96-49-1 ]
  • [ 2233-18-3 ]
  • [ 1039948-89-4 ]
YieldReaction ConditionsOperation in experiment
78.8% With potassium carbonate In N,N-dimethyl-formamide at 110℃; Inert atmosphere The starting material 4-hydroxy-3,5-dimethylbenzaldehyde (1; 70 kg), K2CO3 (9.8 kg) and DMF (133 kg) were mixed and stirred at 110 0C under nitrogen. Ethylene carbonate (45.6 kg) in DMF (46 kg) was added to the mixture over a period of 4 hours, using a diaphragm pump. The reaction mixture was stirred at 110 0C for 12 hours, until less than 5percent of the starting material 1 remained. The reaction mixture <n="17"/>was cooled to 25 0C and water (1300 kg) was added followed by a mixture of dichloromethane and heptane (3V/2V; 1300 kg). The mixture was agitated for 30 minutes. The organic layer was isolated and the aqueous layer was back extracted with a mixture of dichloromethane and heptane (3V/2V; 1300 kg). The combined organic layers were washed with aqueous sodium hydroxide (3 M; 460 kg), followed by three washes with water (3 x 710 kg), and dried over sodium sulfate (60 kg). Dichloromethane was removed from the dried organic layer by distillation, keeping the temperature below 40 0C. Heptane (260 kg) and seed crystals were added to initiate crystallization and the mixture was stirred at 20 0C for 2 hours. The mixture was filtered, washed with heptane (60 kg), and dried under vacuum until constant weight to afford intermediate 2 (71.3 kg, 78.8percent). 1H-NMR (DMSO-d6): δ 9.82 (1 H), 7.54 (2H), 4.96 (1 H), 3.85 (2H), 3.74 (2H), 2.29 (6H).
Reference: [1] Patent: WO2009/158404, 2009, A1, . Location in patent: Page/Page column 15-16
  • 32
  • [ 96-49-1 ]
  • [ 1044870-30-5 ]
  • [ 1044870-39-4 ]
YieldReaction ConditionsOperation in experiment
95% With potassium carbonate In N,N-dimethyl-formamide at 110℃; for 12 h; Compound 10A (3.26 g, 10 mmol) was added to a 100 mL single-mouth bottle.Compound 11 is ethylene carbonate (0.88 g, 10 mmol),Add 30 mL of N,N-dimethylformamide to dissolve it.At the same time, potassium carbonate (1.38 g, 10 mmol) was added.Warm the system to 110 ° C,The reaction was refluxed for 12 hours.After the reaction is over,Add 20 mL of water to the reaction system.Extract three times with dichloromethane (3*20 mL),Combine the organic phase,Dry with anhydrous sodium sulfate,filter,Distilling under reduced pressure to obtain a mixture,Purified by column chromatography (the eluent is petroleum ether / ethyl acetate,Volume ratio 2:1),A yellow solid RVX-208 (3.51 g, yield 95percent) was obtained.
Reference: [1] Patent: CN108484510, 2018, A, . Location in patent: Paragraph 0041
  • 33
  • [ 96-49-1 ]
  • [ 114-07-8 ]
  • [ 55224-05-0 ]
Reference: [1] Patent: WO2012/115256, 2012, A1, . Location in patent: Page/Page column 240
  • 34
  • [ 96-49-1 ]
  • [ 3469-69-0 ]
  • [ 1408334-75-7 ]
YieldReaction ConditionsOperation in experiment
53% at 125℃; for 24 h; a.
2-(4-Iodo-pyrazol-1-yl)-ethanol (Intermediate Aa)
A solution of 4-iodopyrazole (14.3 g, 73.9 mmol) and ethylene carbonate (6.83g, 77.6 mmol) in DMF (50 mL) was stirred at 125° C. for 24 h.
The cooled solution was concentrated under vacuum to leave a brown oil.
The residue was purified by FCC using 30-70percent EtOAc in DCM to give the title compound (9.36 g, 53percent). LCMS (Method 3): Rt 2.24 min, m/z 239 [MH+].
53% at 125℃; for 24 h; A solution of 4-iodopyrazole (14.3 g, 73.9 mmol) and ethylene carbonate (6.83g, 77.6 mmol) in DMF (50 mL) was stirred at 125 °C for 24 h. The cooled solution was concentrated under vacuum to leave a brown oil. The residue was purified by FCC, using 30-70percent EtOAc in DCM, to give the title compound (9.36 g, 53percent). LCMS (Method 3): Rt 2.24 min, m/z 239 [MH+].
53% at 125℃; for 24 h; A solution of 4-iodopyrazole (14.3 g, 73.9 mmol) and ethylene carbonate (6.83g, 77.6 mmol) in DMF (50 mL) was stirred at 125°C for 24 h. The cooled solution was concentrated under vacuum to leave a brown oil. The residue was purified by FCC using 30-70percent EtOAc in DCM to give the title compound (9.36 g, 53percent). LCMS (Method 3): Rt 2.24 min, m/z 239 [MH+].
53% at 125℃; for 24 h; A solution of 4-iodopyrazole (14.3 g, 73.9 mmol) and ethylenecarbonate (6.83g, 77.6 mmol) in DMF (50 mL) was stirred at 125 °C for 24 h.The cooled solution was concentrated under vacuum to leave a brown oil. Theresidue was purified by FCC, using 30-70percent EtOAc in DCM, to give the titlecompound (9.36 g, 53percent).

Reference: [1] Patent: US2014/364411, 2014, A1, . Location in patent: Paragraph 0423; 0424
[2] Patent: WO2014/194956, 2014, A1, . Location in patent: Page/Page column 42
[3] Patent: WO2014/195400, 2014, A1, . Location in patent: Page/Page column 92
[4] Patent: KR2016/16973, 2016, A, . Location in patent: Paragraph 0221-0223
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Reason: Stable Isotope