* 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
[ 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
8
[ 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
9
[ 536-57-2 ]
[ 2216-51-5 ]
[ 1517-82-4 ]
Yield
Reaction Conditions
Operation in experiment
99%
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 25℃; for 16 h; Inert atmosphere
General procedure: To a 250 mL flame-dried N2 purged round-bottomed flask was added p-toluenesulfinic acid (0.525 g, 3.36 mmol), 4-bromobenzyl alcohol (0.598 g, 3.20 mmol), and DMAP (0.078 g, 0.64 mmol) sequentially and dissolved in anhyd CH2Cl2 (14 mL). To the solution was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.644 g, 3.36 mmol) in one portion and stirred for 16 h at r.t. The reaction mixture was diluted with CH2Cl2 (30 mL) and washed with aq 1 M HCl (30 mL) and brine (30 mL). The organic layer was dried (MgSO4), filtered, and solvents removed under reduced pressure. The crude product was purified by flash column chromatography .
Reference:
[1] Synthesis (Germany), 2018, vol. 50, # 24, p. 4855 - 4866
[2] Chemical and Pharmaceutical Bulletin, 1982, vol. 30, # 5, p. 1646 - 1652
[3] Chemical and Pharmaceutical Bulletin, 1982, vol. 30, # 5, p. 1646 - 1652
[4] Molecular Crystals and Liquid Crystals Science and Technology, Section A: Molecular Crystals and Liquid Crystals, 2001, vol. 356, p. 371 - 387
[5] Tetrahedron, 1999, vol. 55, # 8, p. 2311 - 2316
[6] Synthesis, 1978, p. 441 - 442
10
[ 10439-23-3 ]
[ 2216-51-5 ]
[ 98147-48-9 ]
[ 1517-82-4 ]
Yield
Reaction Conditions
Operation in experiment
6 % de
With sulfuric acid In dichloromethane at 25℃; for 4.5 h; Molecular sieve
General procedure: In a test tube containing the appropriate sodium salt of sulfinic acid, 1a-d (1 mmol) was added the appropriate alcohol (1 mL) followed by dichloromethane (4 mL) [For more complex alcohols, 3 equiv. (3 mmol) of alcohol were used]. Under stirring, sulfuric acid (106 mL, 2 equiv.) was added and after 30 min of reaction, powdered 4 Å molecular sieves (200 mg) was added. The mixture was stirred for the time indicated on Table 2 and then diluted with dichloromethane (10 mL) and transferred to a separation funnel. The organic phase was then washed with water (2 x 20 mL), dried over anhydrous MgSO4 and filtered through a pad of silica. The solvents were removed in vacuo and the resulting crude product was further purified by flash column chromatography [hexanes:EtOAc (98:2)].
With triethylamine In dichloromethane at 20℃; Inert atmosphere
General procedure: In a flame-dried, nitrogen purged 100 mL round-bottom flask equipped with magnetic stir bar at room temperature were placed anhydrous toluene sulfinic acid (0.72 g, 4.05 mmol), methylene chloride (12 mL), and pivaloyl chloride (0.49 mL, 4.00 mmol). The resulting mixture was allowed to stir for 5 hours. After the allocated time, triethylamine (0.67 mL, 4.8 mmol) and the alcohol substrate were added. The resulting mixture was allowed to sit overnight and quenched the following day. The mixture was extracted with dichloromethane and 1M HCl. The combined organic layers were washed with brine and dried over anhydrous MgSO4. The solvents were removed in vacuo and the crude product was purified by flash chromatography.
Reference:
[1] Tetrahedron, 1978, vol. 34, p. 63 - 66
[2] Journal of Organic Chemistry, 1967, vol. 32, p. 2059 - 2062
[3] Agricultural and Biological Chemistry, 1985, vol. 49, # 3, p. 671 - 676
18
[ 2216-51-5 ]
[ 158009-86-0 ]
[ 2943-42-2 ]
[ 1517-82-4 ]
[ 37088-67-8 ]
Reference:
[1] Journal of Organic Chemistry, 1995, vol. 60, # 21, p. 7037 - 7039
[2] Journal of Organic Chemistry, 1995, vol. 60, # 21, p. 7037 - 7039
19
[ 2216-51-5 ]
[ 824-79-3 ]
[ 1517-82-4 ]
Reference:
[1] Canadian Journal of Chemistry, 1985, vol. 63, p. 1263 - 1267
20
[ 923031-01-0 ]
[ 923031-02-1 ]
[ 2216-51-5 ]
[ 867-56-1 ]
[ 61597-98-6 ]
Yield
Reaction Conditions
Operation in experiment
51.71%
With sodium hydroxide; water In n-heptane at 15 - 60℃; for 0.6 - 3.6 h;
Preparation of l-Menthyl Lactate by Esterification and Controlled HydrolysisEsterification: A three-neck flask equipped with a Barrett trap, reflux condenser, thermocouple, heating mantle, and magnetic stirrer is charged with l-menthol (1440 g), L-(+)-lactic acid (2880 g of grade HS-88 from Purac, 88percent lactic acid in water), and heptane (720 g). The stirred mixture is brought to reflux and water is periodically drained from the trap as it forms. The temperature of the mixture increases gradually to 128° C. after 32 h and after 854 mL of aqueous phase has been removed. The mixture is cooled to ambient temperature and analyzed by gas-liquid chromatography (GC). It contains: 5.4percent of unreacted menthol, 67.7percent of l-menthyl L-lactate (ML), 0.6percent of lactide (cyclic dimer of lactic acid), 24.6percent of l-menthyl L-lactoyl-L-lactate (MLL), and 0.4percent of l-menthyl L-lactoyl-L-lactoyl-L-lactate (MLLL).Controlled hydrolysis: The esterified product is diluted with water (4230 g) and heptane (960 g). Aqueous sodium hydroxide (809 g of 50percent NaOH) is then added dropwise over 30 min. while the mixture is stirred and cooled (cold water bath) so that the temperature does not exceed 30° C. and the pH does not exceed 12.9. After the base addition, the mixture stirs for another 20 min. GC analysis shows practically complete conversion of MLL into ML. The layers are separated. The organic layer is washed with 1.5percent aqueous lactic acid (1000 g) and then cohobated to remove moisture. The solvent (heptane) is stripped, and the residue is fractionally distilled under vacuum with the following results:Fraction 1, 100 g, 94.5percent menthol and 2.0percent of ML.Fraction 2, 111 g, 46.8percent menthol, 51.8percent ML.Fraction 3, 1860 g, 99.5percent pure ML.Yield of ML contained in all three fractions based on charged menthol: 91percent. Yield of purified ML based on reacted menthol: 98percent; Preparation of l-Menthyl Lactate by Sulfuric Acid-Catalyzed Esterification and Controlled HydrolysisEsterification: The procedure of Example 1 is generally followed using 1000 g of l-menthol, 1000 g of L-(+)-lactic acid, 500 g of heptane, and 6 g of concentrated sulfuric acid. The temperature of the mixture increases gradually to 119° C. after 2 h and after 300 mL of aqueous phase has been removed. The mixture is cooled and analyzed by GC. It contains: 6.4percent of unreacted menthol, 57.6percent of ML, 0.4percent of lactide, 32.2percent of MLL, and 1.9percent of MLLL.Controlled hydrolysis: The esterified product is diluted with water (800 g) and heptane (500 mL). Aqueous sodium hydroxide (204 g of 50percent NaOH) is then added dropwise over 70 min. while the mixture is stirred and cooled (cold water bath) so that the temperature does not exceed 30° C. and the pH does not exceed 13.1. The layers are separated. The organic layer is diluted with water (1350 g) and treated with more 50percent aq. sodium hydroxide (150 g), which is added dropwise over 1 h in the manner described above. After the base addition, the mixture stirs for about 1 h. GC analysis shows practically complete conversion of MLL into ML. The layers are separated. The organic layer is washed with water.The entire procedure of esterification and controlled hydrolysis is repeated. The washed organic layers are combined, the solvent (heptane) is stripped, and the residue is fractionally distilled under vacuum with the following results:Fraction 1, 203 g, 87.1percent menthol, 3.5percent ML, and 6.2percent menthenes.Fraction 2, 96.8 g, 57.2percent menthol, 41.6percent ML.Fraction 3, 2356 g, 99.4percent pure ML.Yield of ML contained in all three fractions based on charged menthol: 81percent. Yield of purified ML based on reacted menthol: 91percent; Controlled Hydrolysis: Normal Mode of AdditionThese examples illustrate that desirable results are obtained by addition of the aqueous base to the esterification mixture at various temperatures at pH below 14.General procedure. In a 500-mL flask equipped with a magnetic stirrer, thermocouple, and pH probe, crude ML (88.7 g, obtained as described above in Example 3) is mixed with water (89 g) and heptane (20 g). The mixture is brought to the test temperature using a thermostat. While stirring, 50percent aq. NaOH (35.5 g) is then pumped gradually (0.6-3.6 hours) into the thermostatted flask, and pH is recorded periodically. After base addition, the mixture is agitated for several minutes until the GC peak corresponding to MLL drops below 1percent. Results appear in Table 1; Reverse AdditionThese examples illustrate that less desirable results are obtained when the esterification mixture is added to the aqueous base (i.e., reverse addition), with pH reaching or exceeding 14.General Procedure. Aqueous NaOH (35.5 g of 50percent solution) is charged to a 500-mL flask equipped with a magnetic stirrer, thermocouple, and pH probe. The stirred mixture is brought to the test temperature using a thermostat. In a separate flask, crude ML (88.7 g, obtained as described in Example 3) is mixed with water (89 g) and heptane (20 g). The stirred mixture is pumped over 0.6-3.6 hours into the thermostatted flask containing aqueous base. Results appear in Table 2; This example illustrates that too much aqueous base gives a less desirable result even with normal addition.The procedure of Example 7 is followed, except that 50 g of aqueous 50percent NaOH is used instead of 35.5 g. The composition of the reaction mixture (GC) is as follows: 44.81percent of l-menthol, 55.05percent ML, and 0.14percent of MLL.
With pyridine; diethyl chlorophosphate; at 70℃; for 3h;Inert atmosphere; Neat (no solvent);
(a) Typical procedure for the synthesis of l-menthol-4-chloro cinnamate, 8d: to a mixture of 4-chlorocinnamic acid (0.365 g, 2.00 mmol) and l-menthol (0.312 g, 2.00 mmol) in pyridine (3.0 mL) was added diethyl chlorophosphate (0.320 mL, 2.10 mmol) slowly at rt in an atmosphere of argon, and the reaction mixture was stirred at rt for about 30 min. The heterogenous mixture was heated at 70 C under argon atmosphere for 3 h, during which the reaction mixture became homogeneous. Pyridine was removed in vacuo, and the residue partitioned between ethyl acetate (15.0 mL) and saturated sodium bicarbonate (5.0 mL). After stirring well (10 min), the organic layer was separated, dried over anhyd Na2SO4 and the solvent evaporated in vacuo to yield the crude product. In all cases, crude products were >95% pure by 1H NMR. Purification of 8d over silica-gel (5% ethyl acetate in hexane) afforded 0.552 g, 86% yield of pure product 8d.
With toluene-4-sulfonic acid; In toluene; for 18h;Dean-Stark; Reflux; Inert atmosphere; Glovebox;
Acetylene dicarboxylic acid (1.00 g, 8.77 mmol), (-)-menthol (3.43 g, 21.9 mmol, 2.50 equiv), p-toluenesulfonic acid (0.167 mg, 0.877 mmol, 0.100 equiv), and toluene (25 mL) were charged in a round-bottomed flask equipped with a Dean- Stark apparatus. The solution was heated under reflux for 18 h. The solution was cooled to rt, washed with water (20 mL x 2) and brine (20 mL), dried (Na2S04), filtered, and concentrated, and the crude material was purified by column chromatography (hexanes:EtOAc 40: 1 , Rf = 0.2) to give the product dimenthyl acetylenedicarboxylate A as a white solid (1.72 g, 4.40 mmol, 50%), as indicated in FIG. 13.
With hydrogen; at 75 - 80℃; under 30003.0 Torr;Product distribution / selectivity;
Example 2 Example 1 was repeated using L-<strong>[7786-67-6]isopulegol</strong> with a purity of 99.9% by weight and 99.8% ee, which was introduced at a rate of 12.6 g/h (total amount 303 g) into the reactor at a hydrogen pressure of 40 bar. The main reactor (MR) was heated to 80 C., the postreactor to 75 C. L-menthol (99.8% ee) was obtained in an amount of 306 g corresponding to a rate of 12.8 g/h. The chemical purity of the L-menthol output is compiled in Table 2.
With hydrogen;50percent NiO, 17percent CuO, 30.5percent ZrO2, 1.5percent MoO3, 1percent graphite; activated by H2 at 180 C; at 85℃; under 30003.0 Torr;Product distribution / selectivity;
EXAMPLE 17; A hydrogenation apparatus consisting of a main reactor (MR) and a postreactor (PR) was used. The main reactor had 5 tubes, connected in series, having an internal diameter of 5 mm and a length of 1.3 m, which were filled with 61 g (127 ml) of a fixed-bed catalyst comprising 50% by weight of NiO, 17% by weight of CuO, 30.5% by weight of ZrO2, 1.5% by weight of MoO3 and 1% by weight of graphite in the form of tablets with a diameter and a height of in each case 3 mm. The postreactor (jacketed) consisted of a tube with an internal diameter of 5 mm and a length of 2.05 m, which was filled with 19 g of the same catalyst.The fixed-bed catalyst installed in the main reactor and postreactor, comprising 50% by weight of NiO, 17% by weight of CuO, 30.5% by weight of ZrO2, 1.5% by weight of MoO3 and 1% by weight of graphite, was activated by the following method. The reactors were heated to 180 C. under ambient pressure with 42 l(STP)/h of nitrogen and 1.2 l(STP)/h of hydrogen, and kept under these conditions for 19 h. The hydrogen was increased from 1.2 to 6.5 l(STP)/h, and the reactor was kept at a temperature of 180 C. for a further 7.5 h. The nitrogen feed was turned off and the activation was continued with 6.5 l(STP)/h of hydrogen at 180 C. for 12 h. The hydrogen feed was then turned off and the nitrogen feed was adjusted to 6 l(STP)/h. The reactors were cooled to a temperature of 60 C. The hydrogen feed was reduced to 1.6 l(STP)/h and the <strong>[7786-67-6]isopulegol</strong> feed was started.By means of a centrifugal pump, a circulation was pumped through the main reactor at a rate of about 500 g/h at a feed of L-<strong>[7786-67-6]isopulegol</strong> of 24.5 g/h (total amount 588 g) with a purity of 99.9% by weight and 99.8% ee. The hydrogen pressure was kept constant at 40 bar. The main reactor was operated at a temperature of 85 C. and the postreactor at 75 C. All pipelines were provided with electrical trace heating to prevent the crystallization of the enantiomerically pure L-menthol (m.p. 44 C.). This gave L-menthol in an amount of 597 g, corresponding to a rate of 24.9 g/h. The L-menthol obtained in this way (99.8% ee) was analyzed by gas chromatography. The chemical purity of the L-menthol discharge is listed in Table 1.
94.8 g
With Raney nickel; at 70℃; under 18751.9 Torr; for 10h;Inert atmosphere;
Example 45Hydrogenation Reaction of High-Purity 1 -<strong>[7786-67-6]Isopulegol</strong>and Synthesis of High-Purity 1-Menthol10562] In a 500-mL autoclave were added 100.0 g (0.65 mol) of the 1 -<strong>[7786-67-6]isopulegol</strong> obtained in Example 44 and 0.4 g of Raney nickel in a nitrogen atmosphere. Hydrogenation was conducted at a hydrogen pressure of 2.5 MPa and 70 C. for 10 hours. The reaction mixture was filtered, followed by distillation to obtain 94.8 g (0.61 mol, 100% e.e.) of 1-menthol.
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 (
EXAMPLE 7 1000 ml concentrate solution (20 mg sertraline/ml) with menthol flavoring: Sertraline HCl: 22.4 g Ethanol (95%): 127 g Menthol: 0.01-1.7 g Glycerin: 852-872 g or sufficient quantity to produce 1000 ml Dissolve the menthol and drug in a mixture of ethanol and glycerin.
EXAMPLE 18 Sertraline HCl: 22.7 g Ethanol, 95%: 151.0 g Menthol: 0.5 g 1N sodium hydroxide: 0.03 g Glycerin: 1010.7 g or sufficient quantity to produce 1000 ml
EXAMPLE 19 Sertraline HCl: 22.7 g Ethanol, 95%: 151.0 g Menthol: 0.5 g Disodium EDTA: 0.1 g Glycerin: 1010.7 g or sufficient quantity to produce 1000 ml
EXAMPLE 29 Sertraline HCl: 22.7 g Ethanol, 95%: 151.0 g Menthol: 0.5 g Disodium EDTA: 0.1 g BHT: 0.1 g BHA: 0.1 g Glycerin: 1010.7 g or sufficient quantity to produce 1000 ml
51
titanium(IV) tetraethanolate[ No CAS ]
[ 2216-51-5 ]
[ 302912-31-8 ]
[ 450844-51-6 ]
Yield
Reaction Conditions
Operation in experiment
92%
In ethyl acetate;
EXAMPLE 93A (1R,2S,5R)-2-isopropyl-5-methylcyclohexyl (4-cyanophenyl)(oxo)acetate A mixture of ethyl (4-cyanophenyl)(oxo)acetate (35.2 g, 173 mmol), (1R,2S,5R)-(-)-menthol (41.0 g, 262 mmol), and titanium ethoxide (3.6 mL, 17 mmol) was heated to 80 C. under vacuum for 60 hours. The mixture was diluted with MTBE (1.5 L), washed sequentially with 10% HCl (2*300 mL), saturated aqueous NaHCO3, and brine, dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 2% ethyl acetate/hexanes to provide the desired product (50.0 g, 92% yield). 1H NMR (CDCl3) delta8.12 (m, 2H), 7.82 (m, 2H), 5.01 (ddd, 2H), 2.15 (m, 1H), 1.91 (m, 1H), 1.72 (m, 2H), 1.55 (m, 2H), 1.16 (m, 2H), 0.97(d, 3H), 0.91 (d, 3H), 0.83 (d, 3H).
92%
In ethyl acetate;
EXAMPLE 93A (1R,2S,5R)-2-isopropyl-5-methylcyclohexyl (4-cyanophenyl)(oxo)acetate A mixture of ethyl (4-cyanophenyl)(oxo)acetate (35.2 g, 173 mmol), (1R,2S,5R)-(-)-menthol (41.0 g, 262 mmol), and titanium ethoxide (3.6 mL, 17 mmol) was heated to 80 C. a under vacuum for 60 hours. The mixture was diluted with MTBE (1.5 L), washed sequentially with 10% HCl (2*300 mL), saturated aqueous NaHCO3, and brine, dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 2% ethyl acetate/hexanes to provide the desired product (50.0 g, 92% yield). 1H NMR (CDCl3) delta 8.12 (m, 2H), 7.82 (m, 2H), 5.01 (ddd, 2H), 2.15 (m, 1H), 1.91 (m, 1H), 1.72 (m, 2H), 1.55 (m, 2H), 1.16 (m, 2H), 0.97(d, 3H), 0.91 (d, 3H), 0.83 (d, 3H).
EXAMPLE 7 Menthyl 2-cyano-3,3-diphenylacrylate 55.4 g (0.2 mol) of <strong>[5232-99-5]ethyl 2-cyano-3,3-diphenylacrylate</strong> (Uvinul 3035), 62.5 g of menthol and 4 g of Na2CO3 were reacted with one another at 185-200 C. with distillative removal of the ethanol formed, assisted by a stream of nitrogen. After about 6 h, the reaction mixture was cooled and distilled under reduced pressure, giving 44 g (57%) of menthyl 2-cyano-3,3-diphenylacrylate [lambdamax=300 nm, E11=351].
Example 6 Preparation of L-menthyl trans-2-methyl-2-pentenoate To a 100-mL round-bottomed flask <strong>[16957-70-3]trans-2-methyl-2-pentenoic acid</strong> (11.4 g, 100 mmol) and thionyl chloride (18 mL, 210 mmol) were added. Bubbles evolved from the light-yellow solution immediately. The mixture was stirred at room temperature for 5 min and then heated to reflux for 30 min, during which time the mixture turned brown. Unreacted thionyl chloride was removed by distillation. L-menthol (15.4 g, 99 mmol) was added to the formed acyl chloride and the mixture was heated in a 160° C. oil bath of for 1 hour, at which time the evolution of HCl ceased. The mixture was transferred into a separatory funnel and the flask rinsed with hexanes (100 mL). The hexanes solution was then washed with aqueous NaHCO3 solution and water. Removal of hexanes in vacuo followed by vacuum distillation gave a light yellow oil, 18.7 g; yield: 75percent.
With sodium hydroxide; water; In n-heptane; at 15 - 60℃; for 0.6 - 3.6h;pH 11.65 - 14;Product distribution / selectivity;
Preparation of l-Menthyl Lactate by Esterification and Controlled HydrolysisEsterification: A three-neck flask equipped with a Barrett trap, reflux condenser, thermocouple, heating mantle, and magnetic stirrer is charged with l-menthol (1440 g), L-(+)-lactic acid (2880 g of grade HS-88 from Purac, 88% lactic acid in water), and heptane (720 g). The stirred mixture is brought to reflux and water is periodically drained from the trap as it forms. The temperature of the mixture increases gradually to 128 C. after 32 h and after 854 mL of aqueous phase has been removed. The mixture is cooled to ambient temperature and analyzed by gas-liquid chromatography (GC). It contains: 5.4% of unreacted menthol, 67.7% of l-menthyl L-lactate (ML), 0.6% of lactide (cyclic dimer of lactic acid), 24.6% of l-menthyl L-lactoyl-L-lactate (MLL), and 0.4% of l-menthyl L-lactoyl-L-lactoyl-L-lactate (MLLL).Controlled hydrolysis: The esterified product is diluted with water (4230 g) and heptane (960 g). Aqueous sodium hydroxide (809 g of 50% NaOH) is then added dropwise over 30 min. while the mixture is stirred and cooled (cold water bath) so that the temperature does not exceed 30 C. and the pH does not exceed 12.9. After the base addition, the mixture stirs for another 20 min. GC analysis shows practically complete conversion of MLL into ML. The layers are separated. The organic layer is washed with 1.5% aqueous lactic acid (1000 g) and then cohobated to remove moisture. The solvent (heptane) is stripped, and the residue is fractionally distilled under vacuum with the following results:Fraction 1, 100 g, 94.5% menthol and 2.0% of ML.Fraction 2, 111 g, 46.8% menthol, 51.8% ML.Fraction 3, 1860 g, 99.5% pure ML.Yield of ML contained in all three fractions based on charged menthol: 91%. Yield of purified ML based on reacted menthol: 98%; Preparation of l-Menthyl Lactate by Sulfuric Acid-Catalyzed Esterification and Controlled HydrolysisEsterification: The procedure of Example 1 is generally followed using 1000 g of l-menthol, 1000 g of L-(+)-lactic acid, 500 g of heptane, and 6 g of concentrated sulfuric acid. The temperature of the mixture increases gradually to 119 C. after 2 h and after 300 mL of aqueous phase has been removed. The mixture is cooled and analyzed by GC. It contains: 6.4% of unreacted menthol, 57.6% of ML, 0.4% of lactide, 32.2% of MLL, and 1.9% of MLLL.Controlled hydrolysis: The esterified product is diluted with water (800 g) and heptane (500 mL). Aqueous sodium hydroxide (204 g of 50% NaOH) is then added dropwise over 70 min. while the mixture is stirred and cooled (cold water bath) so that the temperature does not exceed 30 C. and the pH does not exceed 13.1. The layers are separated. The organic layer is diluted with water (1350 g) and treated with more 50% aq. sodium hydroxide (150 g), which is added dropwise over 1 h in the manner described above. After the base addition, the mixture stirs for about 1 h. GC analysis shows practically complete conversion of MLL into ML. The layers are separated. The organic layer is washed with water.The entire procedure of esterification and controlled hydrolysis is repeated. The washed organic layers are combined, the solvent (heptane) is stripped, and the residue is fractionally distilled under vacuum with the following results:Fraction 1, 203 g, 87.1% menthol, 3.5% ML, and 6.2% menthenes.Fraction 2, 96.8 g, 57.2% menthol, 41.6% ML.Fraction 3, 2356 g, 99.4% pure ML.Yield of ML contained in all three fractions based on charged menthol: 81%. Yield of purified ML based on reacted menthol: 91%; Controlled Hydrolysis: Normal Mode of AdditionThese examples illustrate that desirable results are obtained by addition of the aqueous base to the esterification mixture at various temperatures at pH below 14.General procedure. In a 500-mL flask equipped with a magnetic stirrer, thermocouple, and pH probe, crude ML (88.7 g, obtained as described above in Example 3) is mixed with water (89 g) and heptane (20 g). The mixture is brought to the test temperature using a thermostat. While stirring, 50% aq. NaOH (35.5 g) is then pumped gradually (0.6-3.6 hours) into the thermostatted flask, and pH is recorded periodically. After base addition, the mixture is agitated for several minutes until the GC peak corresponding to MLL drops below 1%. Results appear in Table 1; Reverse AdditionThese examples illustrate that less desirable results are obtained when the esterification mixture is added to the aqueous base (i.e., reverse addition), with pH reaching or exceeding 14.General Procedure. Aqueous NaOH (35.5 g of 50% solution) is charged to a 500-mL flask equipped with a magnetic stirrer, thermocouple, and pH probe. The stirred mixture is brought to the test temperature using a thermostat. In a separate flask, crude ML (88.7 g, obtained as described in Example 3) is mixed with water (89 g) and heptane (20 g). The stirred mixture is pumped over 0.6-3.6 hours into the thermostatted flask containing aqueo...
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.
With tetrafluoroboric acid dimethyl ether complex; In tetrachloromethane; for 4.5h;
(-)-(1R,2S,5R)-Menthol (1.000 g, 6.40 mmol, mp 42.5-43.7 C) and sulfonimidate 1 (2.017 g, 7.04 mmol) were dissolved in magnetically stirred, anhydrous CCl4 (20 mL) in a septum-capped 50-mL round bottom flask with a drying tube. HBF4·OMe2 (66 muL, 0.64 mmol) was added [TLC (hexane-EtOAc, 4:1 + 1% Et3N) monitoring]. After 4.5 h, the mixture was flash chromatographed (silica gel, 5 cm, 1-cm diameter column) to kill the catalyst and remove the sulfonamide byproduct 2. The reaction flask was rinsed with pentane (3 × 5 mL) and flushed through the column. Solvent was removed by rotary evaporation, followed by evacuation under high vacuum to give the product; yield: 0.846 g (72%). The average optical rotation for the product (three determinations) was [alpha]D -95.6 at 20.2 C. The structure was confirmed by 1H NMR (400 MHz) and GC/MS.
(R)-2-hydroxy-3-methylbutyric acid menthyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With acetyl chloride; In toluene; acetonitrile; at 40 - 100℃; for 1h;Inert atmosphere;
2-Hydroxy-3-methylbutyric acid (3 mg) obtained by acid hydrolysis of 1b was dissolved in 300 muL of acetonitrile, and 100 muL of (-)-menthol solution was added. The solution was taken to dryness under a gentle stream of nitrogen at 40 C. After adding 20 muLof toluene and 3 muL of acetyl chloride, the resulting mixture was heated at 100C for 1 h, taken to dryness, and dissolved in toluene (100 muL) for directanalysis by GC-MS.Each of the standard chiral acids, (R)-2-hydroxy-3-methylbutyric acid(3 mg), (S)-2-hydroxy-3-methylbutyric acid(3 mg), and a mixture of both (1.5 mg each) were dissolved in 300 muL MeCN and reacted with (-)-menthol asdescribed above.
(1′R,2′S,5′R,2E,4E,6E)-2′-isopropyl-5′-methylcyclohex-1′-yl deca-2,4,6-trienoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
67%
In toluene; at 110℃; for 3h;
General procedure: To a mixture of alcohol (1 eq., 0.1-0.3 M) and Bestmann ylide (1 eq.) in solvent (toluene ortetrahydrofuran) heated at reflux, a solution of aldehyde (1 eq., 1.0 M) was added. Thereaction was heated at reflux until full consumption of starting material aldehyde wasobserved by TLC. After cooling to r.t., the reaction was concentrated and purified by silicacolumn chromatography to afford the respective product as a colourless to very pale yellowoil
1-bromo-4-[(1S,2S,5R)-5-methyl-2-(propan-2-yl)cyclohexyl]oxy}phthalazine[ No CAS ]
4-bromo-2-[(1S,2S,5R)-5-methyl-2-(propan-2-yl)cyclohexyl]phthalazin-1(2H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
28%; 29%
With triphenylphosphine; diethylazodicarboxylate; In tetrahydrofuran; toluene; at -20 - 20℃; for 25h;Inert atmosphere;
General procedure: Method A The Mitsunobu reaction was carried out under argon. Diethyl azodicarboxylate (1.03 mmol, solution in toluene c?40%) was slowly added to a stirred solution of triphenylphosphine (1.03 mmol) in dry THF (10mL) at the temperature between -10C and -5C. Then a solution of phthalazinone 2 (0.684 mmol) in THF (10 mL) was added dropwise. The whole lot was mixed for 15 min at this temperature and next the appropriate alcohol (0.753 mmol) in THF (5 mL) was added at -10 to -5C. The mixture was stirred during 2 h at this conditions, after, which time the reaction mixture was warmed to ambient temperature and stirred in this conditions for 24h. All volatile materials were removed under reduced pressure, ethyl ether (5 mL) was added to the residue, and the whole lot was stirred for 0.5 h at an ambient temperature. The separate white solid was collected by flirtation and washed with ether, and the filtrate was evaporated to dryness. The product was separated and purified by flash chromatography. Method B The Mitsunobu reaction was carried out under argon. To a round bottom flask were added phthalazinone 2 or 3 (1.78 mmol), alcohol (2.67 mmol), triphenylphosphine (2.67 mmol) and THF (40 mL). Then, the solution was cooled to the temperature -20C for 15 min and diethyl azodicarboxylate (2.67mmol, solution in toluene c?40%) was added dropwise to the solution. The reaction was stirred at -20C for 1h, and then the cold bath allowed to slowly warm to an ambient temperature and stirred in this conditions for 24h. All volatile materials were removed under reduced pressure, diethyl ether (15 mL) was added to the residue, and the whole lot was stirred for 0.5 h at an ambient temperature. The separate white solid was collected by flirtation and washed with ether, and the filtrate was evaporated to dryness. The product was separated and purified by flash chromatography.
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃;
Under ice-water bath, 1.560g (-) - menthol, 1.928g EDC, 60ml of dichloromethane, 1.870g (±)-3-carbamoylmethyl -5-methylhexanoic acid and 1.222g DMAP were added to 250 ml eggplant-shaped flask, stirred at room temperature overnight. Workup: 140ml of dichloromethane was added to the reaction system, and then washed with 3 * 20ml water, the organic phase was dried over anhydrous Na2SO4, filtered, and concentrated to give the crude product. Testing chromatography of the crude product liquid see Figure 1. Using preparative liquid chromatography on the crude esterification reaction product obtained in Example 1 was separated and purified, respectively, to give 1.436g (4a) and 1.416g (4b), total 87.8% yield.
tert-butyl 2-(3-nitrobenzamido)nicotinate[ No CAS ]
[ 464216-16-8 ]
[ 52682-09-4 ]
Yield
Reaction Conditions
Operation in experiment
76%
With acetic acid tert-butyl ester; Zn(2+)*2C2H3O2(1-)*17H2O; at 50℃; for 48.0h;
N-(Pyridin-2-yl)amides 1, such as tert-butyl 2-amidonicotinates 4, can undergo catalytic directed cleavage at room temperature to 140 00 with a primary, secondary or tertiary aliphatic or aromatic alcohol nucleophile 11 (1 .0 equiv to suprastoichiometric amounts) in the presence of a metal catalyst and in the presence or absence of a reaction solvent towards the corresponding esters 13. Based on the general scheme depicted Example Scheme E3, the following examples can be listed (with R? =R?):_Using 8.0 mol% Zn(OAc)2.1 7H20, 1.0 equiv 4, 3.0 equiv 11, tBuOAc, 50 c 48 h(1 R,2S,5R)-2-Isopropyl-5-methylcyclohexyl 3-nitrobenzoate (L-Menthyl 3-n itrobenzoate) (1 3f) was obtained in 76% (0.233 g, 0.763 mmol) yield. Reaction time: 48 h. Colorless oil. 130-NMR (100 MHz, 0D013): : 164.0, 148.3, 135.3, 132.6, 129.6, 127.2, 124.5, 76.1, 47.1, 40.9, 34.2, 31.5, 26.5, 23.5, 22.0, 20.8, 16.5.
(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl 2,2-bis(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl 2,2-bis((1R,2S,5R)-2-isopropyl-5-methylcyclohexyloxy)acetate[ No CAS ]
With sulfuric acid; In 5,5-dimethyl-1,3-cyclohexadiene; for 4h;Heating; Dean-Stark;
2.5 g (16 mmol) of l-menthol (1) and 332.8 mg (3.2 mmol) of (3R)-3-hydroxybutanoic acid (2) were dissolved in 50 g of xylene, and 62.8 mg 0.64 mmol) of sulfuric acid was added and the reaction was carried out with heating for 4 hours while removing the water produced by Dean-Stark tube. (3R)-3-hydroxybutanoic acid-l-menthyl was obtained in 82% yield (based on (3R)-3-hydroxybutanoic acid), and no change in the enantiomeric excess ratio was observed before and after the reaction.
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 [Ru(PnOct3)H2]; In o-xylene; at 130℃; under 375.038 Torr; for 12h;Inert atmosphere; Autoclave;
Under inert conditions, 404 mg of [Ru(PnOct3)4(H)2],3.6g of <strong>[7786-67-6]isopulegol</strong> and 10ml of o-xylene (anhydrous) were weighed into a 50ml glass autoclave.The reaction mixture was then stirred at an oil bath temperature of 130C under autogenous pressure (0.5 bar positive pressure) for 12 hours.After the reaction, the conversion and yield (area %) of menthone (sum of isomers) were determined by gas chromatography.The conversion rate of <strong>[7786-67-6]isopulegol</strong> is 64.5%,Of which menthol (65.8% (-)-menthol,34.2% (+)-isomenthone isomer mixture)The selectivity is 46.3%.Selectivity of secondary components: menthol 30.2%,<strong>[7786-67-6]Isopulegol</strong> ketone 14.4%Total selectivity (Menthone+Menthol + <strong>[7786-67-6]isopulegol</strong> ketone) 90.9%.