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Chemical Structure| 2216-51-5
Chemical Structure| 2216-51-5
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Product Details of [ 2216-51-5 ]

CAS No. :2216-51-5 MDL No. :MFCD00062979
Formula : C10H20O Boiling Point : -
Linear Structure Formula :- InChI Key :NOOLISFMXDJSKH-KXUCPTDWSA-N
M.W : 156.27 Pubchem ID :16666
Synonyms :
Menthomenthol

Calculated chemistry of [ 2216-51-5 ]

Physicochemical Properties

Num. heavy atoms : 11
Num. arom. heavy atoms : 0
Fraction Csp3 : 1.0
Num. rotatable bonds : 1
Num. H-bond acceptors : 1.0
Num. H-bond donors : 1.0
Molar Refractivity : 49.23
TPSA : 20.23 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : Yes
P-gp substrate : No
CYP1A2 inhibitor : No
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -4.84 cm/s

Lipophilicity

Log Po/w (iLOGP) : 2.63
Log Po/w (XLOGP3) : 3.4
Log Po/w (WLOGP) : 2.44
Log Po/w (MLOGP) : 2.45
Log Po/w (SILICOS-IT) : 2.06
Consensus Log Po/w : 2.59

Druglikeness

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

Water Solubility

Log S (ESOL) : -2.88
Solubility : 0.204 mg/ml ; 0.0013 mol/l
Class : Soluble
Log S (Ali) : -3.5
Solubility : 0.0489 mg/ml ; 0.000313 mol/l
Class : Soluble
Log S (SILICOS-IT) : -1.48
Solubility : 5.22 mg/ml ; 0.0334 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 2.63

Safety of [ 2216-51-5 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P273-P301+P312+P330-P302+P352-P305+P351+P338 UN#:N/A
Hazard Statements:H302-H315-H319-H335-H413 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 2216-51-5 ]

* 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 [ 2216-51-5 ]
  • Downstream synthetic route of [ 2216-51-5 ]

[ 2216-51-5 ] Synthesis Path-Upstream   1~22

  • 1
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YieldReaction ConditionsOperation in experiment
99.9% 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).
Reference: [1] Patent: US2011/81393, 2011, A1, . Location in patent: Page/Page column 10
[2] Molecules, 2005, vol. 10, # 1, p. 81 - 97
[3] Molecular Crystals and Liquid Crystals, 2015, vol. 609, # 1, p. 31 - 39
[4] Patent: US2009/28803, 2009, A1,
  • 2
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YieldReaction ConditionsOperation in experiment
53 % ee 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
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Reference: [1] Journal of the Chemical Society, 1922, vol. 121, p. 2055
  • 4
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  • [ 34212-59-4 ]
Reference: [1] Patent: US7247743, 2007, B1, . Location in patent: Page/Page column 5-6
[2] Patent: US7247743, 2007, B1, . Location in patent: Page/Page column 5-6
  • 5
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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
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Reference: [1] Annales de Chimie (Cachan, France), 1886, vol. <6> 7, p. 483
  • 8
  • [ 110-15-6 ]
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  • [ 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 ]
YieldReaction ConditionsOperation 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
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YieldReaction ConditionsOperation 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)].
Reference: [1] Tetrahedron Letters, 2017, vol. 58, # 13, p. 1265 - 1268
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YieldReaction ConditionsOperation in experiment
48 % de 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 Letters, 2017, vol. 58, # 31, p. 3073 - 3077
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Reference: [1] European Journal of Organic Chemistry, 2001, # 8, p. 1449 - 1458
  • 13
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Reference: [1] Molecular Crystals and Liquid Crystals Science and Technology, Section A: Molecular Crystals and Liquid Crystals, 2001, vol. 356, p. 371 - 387
[2] Journal of Organic Chemistry, 1987, vol. 52, # 12, p. 2598 - 2602
  • 14
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Reference: [1] Advanced Synthesis and Catalysis, 2016, vol. 358, # 23, p. 3863 - 3868
  • 15
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Reference: [1] Tetrahedron, 1991, vol. 47, # 44, p. 9167 - 9178
  • 16
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Reference: [1] Synthesis, 1982, # 7, p. 584 - 586
  • 17
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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
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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
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Reference: [1] Canadian Journal of Chemistry, 1985, vol. 63, p. 1263 - 1267
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YieldReaction ConditionsOperation 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.
Reference: [1] Patent: US7173146, 2007, B1, . Location in patent: Page/Page column 5-8
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  • [ 111969-64-3 ]
Reference: [1] Patent: CN105130806, 2017, B,
[2] Patent: CN107382725, 2017, A,
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  • [ 111969-64-3 ]
Reference: [1] Patent: CN105130806, 2017, B,
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