* 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.
at 110℃; for 8 h; Autoclave; Inert atmosphere; Neat (no solvent)
Synthetic Example 1 Synthesis of l-menthyl-(l-menthoxyethyl)succinic ester Compound 1 To a 100 ml autoclave, 10.00 g (63.99 mmol) of l-menthol and 6.40 g (63.96 mmol) of succinic anhydride were added, flushed with nitrogen gas, and then stirred at 110° C. for 8 hours. After cooling to room temperature, 100 ml of hexane was added thereto. The precipitated crystals were filtered and the filtrate, hexane phase was concentrated to obtain 16.61 g of l-menthylsuccinic acid. The yield was >99.9percent.
78.6%
With dmap In tetrahydrofuran for 12 h; Reflux
(-)- Monomenthyl succinate was synthesized using the common method esterification of (-)-methanol and succinic anhydridein THF with the catalyst DMAP. Yield: 78.6percent. M.p. 61–63 °C.FR-IR (KBr, cm−1): 2917–3440, 1727, 1710, 1388, 1285, 1224, 1177, 1037, 1011. 1HNMR (CDCl3, ppm): .4.67–4.74 (m, 1H), 2.67–2.72 9 (t, 2H), 2.58–2.63 (t, 2H),0.72–2.01 (broad, 18H).
With Candida cylindracea lipase In diethyl ether at 20℃; for 24 h; Schlenk technique; Resolution of racemate; Enzymatic reaction
A dry Schlenk tube was charged with rac-alcohol (1 equivalent) and succinic anhydride (1 equiv.) dissolved in 2 mL of diethyl ether. The reaction was initiated by the addition of 100 mg of CCL. The reaction mixture was shaken at room temperature for 24 h. After removal of the lipase by filtration, the filtrate was shaken with 1 M Na2CO3 solution, and the remaining alcohol and the produced monoester succinate were separated by liquid–liquid extraction. The remaining enantiomer was obtained from the organic layer and the aqueous phase was washed with an organic solvent and treated by adding 1 M NaOH solution to obtain the other enantiomer. The enantiomeric excesses values were quantified by chiral GC analyses. Chiral GC: Chiralsil-DEX CB: (Tcolumn = 120 °C. flow: 1,2 mL/min); dl-(±)-menthyl acetate: td-(+) = 9.58 min; tl-(-) =10.85 min. dl-(±)-menthol: td-(+) = 13.25 min; tl-(-) = 13.69 min.
Reference：
[1] Research on Chemical Intermediates, 2018, vol. 44, # 11, p. 6847 - 6860
3
[ 3878-55-5 ]
[ 2216-51-5 ]
[ 77341-67-4 ]
Reference：
[1] Journal of the Chemical Society, 1922, vol. 121, p. 2055
Reference：
[1] Justus Liebigs Annalen der Chemie, 1931, vol. 488, p. 211,216, 234[2] Justus Liebigs Annalen der Chemie, 1932, vol. 492, p. 266,271
[3] Justus Liebigs Annalen der Chemie, 1931, vol. 488, p. 211,216, 234[4] Justus Liebigs Annalen der Chemie, 1932, vol. 492, p. 266,271
[5] Justus Liebigs Annalen der Chemie, 1931, vol. 488, p. 211,216, 234[6] Justus Liebigs Annalen der Chemie, 1932, vol. 492, p. 266,271
6
[ 110-15-6 ]
[ 2216-51-5 ]
[ 77341-67-4 ]
Reference：
[1] Zhurnal Russkago Fiziko-Khimicheskago Obshchestva, 1902, vol. 34, p. 721[2] Chem. Zentralbl., 1903, vol. 74, # I, p. 162
[3] Journal of the American Pharmaceutical Association (1912-1977), 1938, vol. 27, p. 753
7
[ 92419-65-3 ]
[ 77341-67-4 ]
Reference：
[1] Justus Liebigs Annalen der Chemie, 1931, vol. 488, p. 211,216, 234[2] Justus Liebigs Annalen der Chemie, 1932, vol. 492, p. 266,271
[3] Justus Liebigs Annalen der Chemie, 1931, vol. 488, p. 211,216, 234[4] Justus Liebigs Annalen der Chemie, 1932, vol. 492, p. 266,271
8
[ 89-83-8 ]
[ 77341-67-4 ]
Reference：
[1] Journal of the Chemical Society, 1912, vol. 101, p. 116
[2] Journal of the Chemical Society, 1912, vol. 101, p. 116
9
[ 34212-60-7 ]
[ 77341-67-4 ]
Reference：
[1] Justus Liebigs Annalen der Chemie, 1931, vol. 488, p. 211,216, 234[2] Justus Liebigs Annalen der Chemie, 1932, vol. 492, p. 266,271
[3] Justus Liebigs Annalen der Chemie, 1931, vol. 488, p. 211,216, 234[4] Justus Liebigs Annalen der Chemie, 1932, vol. 492, p. 266,271
10
[ 81177-19-7 ]
[ 77341-67-4 ]
Reference：
[1] Justus Liebigs Annalen der Chemie, 1931, vol. 488, p. 211,216, 234[2] Justus Liebigs Annalen der Chemie, 1932, vol. 492, p. 266,271
11
[ 10458-14-7 ]
[ 77341-67-4 ]
Reference：
[1] Comptes Rendus Hebdomadaires des Seances de l'Academie des Sciences, 1924, vol. 179, p. 405[2] Bulletin de la Societe Chimique de France, 1926, vol. <4> 39, p. 672
12
[ 34675-24-6 ]
[ 77341-67-4 ]
Reference：
[1] Justus Liebigs Annalen der Chemie, 1931, vol. 488, p. 211,216, 234[2] Justus Liebigs Annalen der Chemie, 1932, vol. 492, p. 266,271
13
[ 108-30-5 ]
[ 2216-52-6 ]
[ 77341-67-4 ]
Reference：
[1] Comptes Rendus Hebdomadaires des Seances de l'Academie des Sciences, 1924, vol. 179, p. 405[2] Bulletin de la Societe Chimique de France, 1926, vol. <4> 39, p. 672
14
[ 108-30-5 ]
[ 490-99-3 ]
[ 77341-67-4 ]
Reference：
[1] Journal of the Chemical Society, 1912, vol. 101, p. 116
15
[ 108-30-5 ]
[ 2216-51-5 ]
[ 77341-67-4 ]
[ 115936-72-6 ]
Reference：
[1] Annales de Chimie (Cachan, France), 1886, vol. <6> 7, p. 483
16
[ 110-15-6 ]
[ 2216-51-5 ]
[ 77341-67-4 ]
[ 34212-59-4 ]
Reference：
[1] Journal of the American Pharmaceutical Association (1912-1977), 1938, vol. 27, p. 753
N-{7-[3-((1R,2S,5R)-2-Isopropyl-5-methyl-cyclohexyloxycarbonyl)-propionylamino]-heptyl}-succinamic acid (1R,2S,5R)-2-isopropyl-5-methyl-cyclohexyl ester[ No CAS ]
N-[2-(Bis-{2-[3-((1R,2S,5R)-2-isopropyl-5-methyl-cyclohexyloxycarbonyl)-propionylamino]-ethyl}-amino)-ethyl]-succinamic acid (1R,2S,5R)-2-isopropyl-5-methyl-cyclohexyl ester[ No CAS ]
at 110℃; for 8.0h;Autoclave; Inert atmosphere; Neat (no solvent);
Synthetic Example 1 Synthesis of l-menthyl-(l-menthoxyethyl)succinic ester Compound 1 To a 100 ml autoclave, 10.00 g (63.99 mmol) of l-menthol and 6.40 g (63.96 mmol) of succinic anhydride were added, flushed with nitrogen gas, and then stirred at 110 C. for 8 hours. After cooling to room temperature, 100 ml of hexane was added thereto. The precipitated crystals were filtered and the filtrate, hexane phase was concentrated to obtain 16.61 g of l-menthylsuccinic acid. The yield was >99.9%.
78.6%
With dmap; In tetrahydrofuran; for 12.0h;Reflux;
(-)- Monomenthyl succinate was synthesized using the common method esterification of (-)-methanol and succinic anhydridein THF with the catalyst DMAP. Yield: 78.6%. M.p. 61-63 C.FR-IR (KBr, cm-1): 2917-3440, 1727, 1710, 1388, 1285, 1224, 1177, 1037, 1011. 1HNMR (CDCl3, ppm): .4.67-4.74 (m, 1H), 2.67-2.72 9 (t, 2H), 2.58-2.63 (t, 2H),0.72-2.01 (broad, 18H).
With toluene-4-sulfonic acid; In toluene;
Example 1 Synthesis of Monomenthyl Succinate A 500 ml round bottom flask was charged with succinic anhydride (25 g, 0.25 mol), p-toluene sulfonic acid (1.0 g) and anhydrous toluene (125 ml) and heated to reflux. Menthol (25 g, 0.25 mol) dissolved in anhydrous toluene (100 ml) was added drop-wise to the refluxing solution at 135 C. After the menthol solution was added, the mixture was refluxed for an additional five hours. After cooling to room temperature, the mixture was washed with de-ionized (DI) water (5*200 ml). The toluene was removed by rotary evaporator, followed by removal under high vacuum at 70 C. No menthol was distilled from the crude product at high vacuum (0.1 torr) at 120 C., showing complete conversion to monomenthyl succinate. The crude product was crystallized from hexanes to form white crystals. 1H NMR showed monomenthyl succinate in high purity (
sodium acetate; at 110℃; for 4.8h;Product distribution / selectivity;
Selective Preparation of Monomenthyl Esters: General Procedure; A mixture of l-menthol (50 g, 0.32 mol) and glutaric anhydride (36.5 g, 0.32 mol) or succinic anhydride (32.0 g, 0.32 mol) is heated in the presence of a base catalyst (for examples of the invention) or in the absence of any catalyst (comparative examples). The reaction temperature, catalysts, and amounts are shown in Table 1. The reaction mixtures are periodically sampled and analyzed by gas chromatography (GC) to measure the conversion of menthol to the monomenthyl and bis-menthyl esters of dicarboxylic acids, i.e., monomenthyl glutarate (MMG) or monomenthyl succinate (MMS). In each case, the ?monoester? reaches a maximum concentration, which slowly decreases thereafter. Maximum monoester concentrations are reported in Table 1.The results demonstrate that the selectivity of the process for making monomenthyl esters is enhanced dramatically (100-200%) simply by including a catalytic amount of a base. Additionally, the reaction time is reduced in the presence of the catalyst. While the maximum monoester concentration is mildly enhanced by using the base catalyst, we surprisingly found that the amount of monomenthyl ester relative to the amount of bis-menthyl ester (or ?diester?) improves substantially when the base catalyst is included.The examples are meant only as illustrations. The following claims define the invention.
at 110℃; for 7.8h;Product distribution / selectivity;
Selective Preparation of Monomenthyl Esters: General Procedure; A mixture of l-menthol (50 g, 0.32 mol) and glutaric anhydride (36.5 g, 0.32 mol) or succinic anhydride (32.0 g, 0.32 mol) is heated in the presence of a base catalyst (for examples of the invention) or in the absence of any catalyst (comparative examples). The reaction temperature, catalysts, and amounts are shown in Table 1. The reaction mixtures are periodically sampled and analyzed by gas chromatography (GC) to measure the conversion of menthol to the monomenthyl and bis-menthyl esters of dicarboxylic acids, i.e., monomenthyl glutarate (MMG) or monomenthyl succinate (MMS). In each case, the ?monoester? reaches a maximum concentration, which slowly decreases thereafter. Maximum monoester concentrations are reported in Table 1.The results demonstrate that the selectivity of the process for making monomenthyl esters is enhanced dramatically (100-200%) simply by including a catalytic amount of a base. Additionally, the reaction time is reduced in the presence of the catalyst. While the maximum monoester concentration is mildly enhanced by using the base catalyst, we surprisingly found that the amount of monomenthyl ester relative to the amount of bis-menthyl ester (or ?diester?) improves substantially when the base catalyst is included.The examples are meant only as illustrations. The following claims define the invention.
Example 5 Conversion of Monomenthyl Succinate to Sodium Monomenthyl Succinate with Sodium Carbonate Monomenthyl succinate (0.5 g, 1.95 mmol) was dissolved in ethanol (6.3 ml). Sodium carbonate solution (0.207 g, 1.95 mmol in 10 ml DI H2O) was slowly added to the monomenthyl succinate solution at room temperature. The mixture was allowed to stir for 19 hours. Water and ethanol were removed by rotary evaporator at 50 C., followed by high vacuum line at 50 C. to give sodium monomenthyl succinate as a fine white powder.
With sodium hydrogencarbonate; In ethanol; water;
Example 6 Conversion of Monomenthyl Succinate to Sodium Monomenthyl Succinate with Sodium Bicarbonate Monomenthyl succinate (0.5 g, 1.95 mmol) was dissolved in ethanol (6.3 ml). Sodium bicarbonate solution (0.196 g, 2.33 mmol in 10 ml DI H2O) was slowly added to the monomenthyl succinate solution at room temperature. The mixture was stirred for 19 hours. Water and ethanol were removed by rotary evaporator at 50 C., followed by high vacuum line at 50 C. to give sodium monomenthyl succinate as a fine white powder.
Example 2 Conversion of Monomenthyl Succinate to Potassium Monomenthyl Succinate Monomenthyl succinate (5.0 g, 19.5 mmol) was added to an aqueous potassium hydroxide solution (1.09 g, 19.5 mmol in 50 ml DI water) at room temperature. The mixture was stirred for two hours until the menthyl succinate completely dissolved. Water was removed by freeze drying to give white powder. Dried samples were tested by thermogravimetric analysis/mass spectrometry (TGA/MS) and gas chromatograph/mass spectrometry (GC/MS). Additionally, a small sample was heated in a vial by heat gun and considerable menthol was released.
With thionyl chloride; N,N-dimethyl-formamide; at 20℃; for 2.0h;
To a 20 ml two-neck flask, 6.00 g (23.42=1) of l-menthylsuccinic acid and 20.0 mg of DMF were added, and 6.00 g (50.43 mmol) of thionyl chloride was added dropwise thereto at room temperature. Upon the completion of the dropwise addition, the mixture was stirred for 2 hours and excess thionyl chloride was removed by distillation under reduced pressure to obtain 6.45 g of l-menthylsuccinic acid chloride. The yield was >99.9%.
With bis(trichloromethyl) carbonate; N,N-dimethyl-formamide; In 1,2-dichloro-ethane; at 50℃; for 16.0h;
In 2000ml four round bottomed flask 1 mol L-succinic acid menthyl ester, 0.02 mol DMF catalyst, 2.5 mol of 1,2-dichloroethane, With sufficient stirring, A solution of triphosgene was added dropwise (2 mol of triphosgene in 5 mol of 1,2-dichloroethane). During the dropwise addition, the internal temperature was maintained at 50 C and stirred for 16 h. The reaction was stopped to obtain menthyl succinate monochloride.
With dmap; dicyclohexyl-carbodiimide; In tetrahydrofuran; at 20℃; for 24.0h;
Ten millimole compound (1) and 32 mmol 4, 4-biphenyl were dissolved in 40 mL dry THF,10 mmol DCC, and 2 mmol DMAP were added with stirring at room temperature for 24 hr. The dicyclohexylurea formed as precipitation was removed by filtration and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatographyon silica gel (200-300 mesh) using a mixture of petroleum ether (60-90 C)and ethyl acetate (4/1, v/v) as eluent, white solid powder was obtained. Yield: 51.4%. mp.135.5-137 C. FR-IR (KBr, cm-1): 3475, 2956, 1751, 1731, 1611, 1530, 1408, 1368, 1267, 1207,1153, 969, 891, 824. 1HNMR (CDCl3, ppm): 7.74-7.49 (d, 2H), 7.37-7.40 (d, 2H),7.09-7.12 (d, 2H), 6.82-6.95 (d, 2H), 5.29 (s, 1H), 4.70-4.79 (m, 1H), 2.89-2.93 (t,4H), 2.73-2.77 (t, 4H), 0.74-2.02 (broad, 18H).
With Candida cylindracea lipase; In diethyl ether; at 20℃; for 24.0h;Schlenk technique; Resolution of racemate; Enzymatic reaction;
A dry Schlenk tube was charged with rac-alcohol (1 equivalent) and succinic anhydride (1 equiv.) dissolved in 2 mL of diethyl ether. The reaction was initiated by the addition of 100 mg of CCL. The reaction mixture was shaken at room temperature for 24 h. After removal of the lipase by filtration, the filtrate was shaken with 1 M Na2CO3 solution, and the remaining alcohol and the produced monoester succinate were separated by liquid-liquid extraction. The remaining enantiomer was obtained from the organic layer and the aqueous phase was washed with an organic solvent and treated by adding 1 M NaOH solution to obtain the other enantiomer. The enantiomeric excesses values were quantified by chiral GC analyses. Chiral GC: Chiralsil-DEX CB: (Tcolumn = 120 C. flow: 1,2 mL/min); dl-(±)-menthyl acetate: td-(+) = 9.58 min; tl-(-) =10.85 min. dl-(±)-menthol: td-(+) = 13.25 min; tl-(-) = 13.69 min.
With bis[3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridyl]phenyl]iridium(1+); 2-(2-pyridyl)pyridine; hexafluorophosphate In dimethyl sulfoxide at 50℃; for 12h; Inert atmosphere; Irradiation;
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