2-(Ethylamino)-2-(2-thienyl)cyclohexanone (Tiletamine)

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6 reactions in Reaxys

2017-08-07 00h:15m:43s (EST)

O

1. Query HN

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2017-08-07 00:53:38

S

H 2N OH

O

HN

racemate

Rx-ID: 42022204 View in Reaxys 1/6 Yield

Conditions & References Reaction Steps: 2 1: sodium cyanoborohydride; acetic acid / methanol / 1.5 h / 0 - 20 °C / |Inert atmosphere 2: Jone's reagent / acetone / 0.5 h / 20 °C / |Inert atmosphere With Jone's reagent, sodium cyanoborohydride, acetic acid in methanol, acetone Sato, Shohei; Takeda, Norihiko; Ueda, Masafumi; Miyata, Okiko; Synthesis (Germany); vol. 48; nb. 6; (2016); p. 882 - 892; Art.No: SS-2015-F0643-OP View in Reaxys

S

NH OH

O

HN

racemate

Rx-ID: 42022207 View in Reaxys 2/6 Yield

Conditions & References

61 mg

2-(Ethylamino)-2-(2-thienyl)cyclohexanone (Tiletamine) To a solution of β-amino alcohol 11aG (53 mg, 0.27 mmol) in MeOH(5.0 mL) was added acetaldehyde (0.018 mL, 0.32 mmol), AcOH (0.016mL, 0.27 mmol), and NaBH3CN (26 mg, 0.41 mmol) successively at0 °C. The mixture was stirred at r.t. for 1.5 h, and then sat. aq Na2CO3(10 mL) was added. The mixture was extracted with Et2O (3 × 15 mL).The combined organic layers were then dried (MgSO4), filtered, andconcentrated in vacuo to afford (1R*,2S*)-2(ethylamino)-2-(2-thienyl)cyclohexanol. This structure was confirmed by 1H NMR; ethylproton signals were observed at δ = 2.44–2.33 (m, 2 H) and 1.07 (t, J =7.0 Hz, 3 H). The above amino alcohol was used in the subsequent reaction without further purification. To the solution of amino alcohol(84 mg) in acetone (20 mL) was slowly added Jones reagent (2.3 M,0.064 mL, 0.15 mmol) at r.t. and the mixture stirred at r.t. for 30 min.After completion of the reaction, the mixture was filtered through apad of Celite (Et2O, 10 mL) and solvent was removed under reducedpressure. The residue was basified with 2.0 M aq NaOH and extractedwith Et2O (3 × 15 mL). The combined organic layers were dried (MgSO4) and concentrated in vacuo. The residue was purified by PTLC(CHCl3–MeOH, 10:1) to give Tiletamine (61 mg, 78percent) as a pale yellowoil.IR (neat): 3329, 1713 cm–1.1H NMR (300 MHz, CDCl3): δ = 7.29 (dd, J = 5.0, 1.0 Hz, 1 H), 6.99 (dd,J = 5.0, 3.5 Hz, 1 H), 6.88 (dd, J = 3.5, 1.0 Hz, 1 H), 2.69 (dm, J = 13.0 Hz,1 H), 2.48 (dd, J = 9.0, 5.5 Hz, 2 H), 2.38 (dq, J = 10.5, 7.0 Hz, 1 H), 2.25(dq, J = 10.5, 7.0 Hz, 1 H), 2.06 (br s, 1 H), 2.03–1.84 (m, 4 H), 1.81–1.69 (m, 1 H), 1.04 (t, J = 7.0 Hz, 3 H).13C NMR (75 MHz, CDCl3): δ = 209.6, 145.4, 126.9, 125.7, 125.2, 67.6,39.0, 38.7, 36.8, 26.9, 22.3, 15.6.HRMS (ESI): m/z [M + H]+ calcd for C12H18NOS: 224.1104; found: 224.1099. With Jone's reagent in acetone, Time= 0.5h, T= 20 °C , Inert atmosphere Sato, Shohei; Takeda, Norihiko; Ueda, Masafumi; Miyata, Okiko; Synthesis (Germany); vol. 48; nb. 6; (2016); p. 882 - 892; Art.No: SS-2015-F0643-OP View in Reaxys

S

O Cl

H

HN

Rx-ID: 24294284 View in Reaxys 3/6 Yield 70%

Conditions & References 6.a : a. a.

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o-Dichlorobenzene as a Solvent for the Acid Addition Salt Reaction Hydrogen chloride gas (2.81 g, 77.16 mmol) was bubbled through a solution of tiletamine (38.58 mmol assumed--the mixture from Example 5) in o-dichlorobenzene, keeping the temperature at about 2° C. The resulting reaction mixture was filtered to produce 3.6 grams of a yellow solid. This solid was vigorously stirred for 30 min in 15 mL of acetone. The mixture was filtered, the solid reaction product was washed with acetone and dried at 40° C. giving 2.3 g of tiletamine hydrochloride (23percent overall process yield through six steps, 99.93percent pure by RP-IPC area percent analysis). The filtrate and acetone wash were combined and subjected to evaporation to recover 4.47 g (36percent corrected yield, 70percent pure by GC area percent analysis) of unreacted free tiletamine. Patent; Great Lakes Chemical Corporation; US5969159; (1999); (A1) English View in Reaxys 70%

5.a : 2-Ethylamino-2(2'-thienyl)cyclohexanone hydrochloride (tiletamine hydrochloride) a. o-Dichlorobenzene as a solvent for the acid addition salt reaction Hydrogen chloride gas (2 81 g, 77.16 mmol) was bubbled through a solution of tiletamine (38.58 mmol assumed--the mixture from Example 4) in o-dichlorobenzene, keeping the temperature at about 2° C. The resulting reaction mixture was filtered to produce 3.6 grams of a yellow solid. This solid was vigorously stirred for 30 min in 15 mL of acetone. The mixture was filtered, the solid reaction product was washed with acetone and dried at 40° C. giving 2.3 g of tiletamine hydrochloride (23percent overall process yield through five steps, 99.93percent pure by RP-IPC area percent analysis). The filtrate and acetone wash were combined and subjected to evaporation to recover 4.47 g (36percent corrected yield, 70percent pure by GC area percent analysis) of unreacted free tiletamine. Patent; Great Lakes Chemical Corporation; US6147226; (2000); (A1) English View in Reaxys 6.b : b. b. Di-n-butyl Ether as a Solvent for the Acid Addition Salt Reaction Hydrogen chloride gas (2.81 g, 77.16 mmol) is bubbled through a solution of tiletamine (38.58 mmol assumed--the mixture from Example 5) in di-n-butyl ether, keeping the temperature at about 2° C. The resulting reaction mixture is filtered to produce about 8.0 grams of a yellow solid. This solid is vigorously stirred for 30 min in 30 mL of acetone. The mixture is filtered, to remove the solid reaction product, the reaction product is washed with acetone and dried at 40° C. giving about 7.0 g of tiletamine hydrochloride. Patent; Great Lakes Chemical Corporation; US5969159; (1999); (A1) English View in Reaxys 5.b : 2-Ethylamino-2(2'-thienyl)cyclohexanone hydrochloride (tiletamine hydrochloride) b. Di-n-butyl ether as a solvent for the acid addition salt reaction Hydrogen chloride gas (2.81 g, 77.16 mmol) is bubbled through a solution of tiletamine (38.58 mmol assumed--the mixture from Example 4) in di-n-butyl ether, keeping the temperature at about 2° C. The resulting reaction mixture is filtered to produce about 8.0 grams of a yellow solid. This solid is vigorously stirred for 30 min in 30 mL of acetone. The mixture is filtered, to remove the solid reaction product, the reaction product is washed with acetone and dried at 40° C. giving about 7.0 g of tiletamine hydrochloride. Patent; Great Lakes Chemical Corporation; US6147226; (2000); (A1) English View in Reaxys

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S

H 2N

O Cl

OH

H

HN

racemate

Rx-ID: 42022205 View in Reaxys 4/6 Yield

Conditions & References Reaction Steps: 3 1: sodium cyanoborohydride; acetic acid / methanol / 1.5 h / 0 - 20 °C / |Inert atmosphere 2: Jone's reagent / acetone / 0.5 h / 20 °C / |Inert atmosphere 3: hydrogenchloride / water; diethyl ether / 2 h / 0 °C / |Inert atmosphere With hydrogenchloride, Jone's reagent, sodium cyanoborohydride, acetic acid in methanol, diethyl ether, water, acetone Sato, Shohei; Takeda, Norihiko; Ueda, Masafumi; Miyata, Okiko; Synthesis (Germany); vol. 48; nb. 6; (2016); p. 882 - 892; Art.No: SS-2015-F0643-OP View in Reaxys

S

NH OH

O Cl

H

HN

racemate

Rx-ID: 42022208 View in Reaxys 5/6 Yield

Conditions & References Reaction Steps: 2 1: Jone's reagent / acetone / 0.5 h / 20 °C / |Inert atmosphere 2: hydrogenchloride / water; diethyl ether / 2 h / 0 °C / |Inert atmosphere With hydrogenchloride, Jone's reagent in diethyl ether, water, acetone Sato, Shohei; Takeda, Norihiko; Ueda, Masafumi; Miyata, Okiko; Synthesis (Germany); vol. 48; nb. 6; (2016); p. 882 - 892; Art.No: SS-2015-F0643-OP View in Reaxys

S

O

O Cl

HN

H

HN

Rx-ID: 42022209 View in Reaxys 6/6 Yield 100 %

Conditions & References 2-(Ethylamino)-2-(2-thienyl)cyclohexanone Hydrochloride (Tiletamine Hydrochloride) Tiletamine (15 mg, 0.065 mmol) was stirred in 1.0 M HCl in Et2O (2.0mL) at 0 °C. The mixture was stirred at 0 °C for 2 h, then it was concentrated under reduced pressure to give Tiletamine hydrochloride(17 mg, quant) as a white solid. The 1H NMR spectrum of syntheticTiletamine hydrochloride was found to be identical to that of commercially available Tiletamine hydrochloride by Toronto ResearchChemicals Inc.; mp 182–185 °C (dec.).IR (CHCl3): 1725 cm– 1.1H NMR (500 MHz, DMSO-d6): δ = 9.97 (br s, 1 H), 9.30 (br s, 1 H), 7.84(d, J = 4.5 Hz, 1 H), 7.21–7.18 (m, 2 H), 2.92 (dm, J = 13.0 Hz, 1 H),2.68–2.64 (m, 1 H), 2.53–2.33 (m, 4 H), 1.98–1.94 (m, 1 H), 1.18 (dm,J = 13.0 Hz, 1 H), 1.73–1.57 (m, 2 H), 1.15 (t, J = 7.0 Hz, 3 H).13C NMR (125 MHz, DMSO-d6): δ = 204.1, 134.2, 130.5, 129.8, 128.1,68.2, 38.5, 37.2, 34.7, 26.2, 21.4, 11.2.HRMS (ESI): m/z [M – HCl]+ calcd for C12H18NOS: 224.1104; found: 224.1102. With hydrogenchloride in diethyl ether, water, Time= 2h, T= 0 °C , Inert atmosphere Sato, Shohei; Takeda, Norihiko; Ueda, Masafumi; Miyata, Okiko; Synthesis (Germany); vol. 48; nb. 6; (2016); p. 882 - 892; Art.No: SS-2015-F0643-OP View in Reaxys

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