9,10-Didehydro-6-methylergoline-8β-carboxylic acid [(+)-lysergic acid] [CAS 82-58-6; InChIKey

Query Query

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Date

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2016-03-05 01h:33m:35s (EST)

O

1. Query

OH HN

N H

Search as: As drawn

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O

O O

HN

OH

HN

N

N

H

H

Rx-ID: 30666960 View in Reaxys 1/20 Yield

Conditions & References

78.4 %

With water, sodium hydroxide in ethanol, Time= 2h, T= 40 °C Umezaki, Satoshi; Yokoshima, Satoshi; Fukuyama, Tohru; Organic Letters; vol. 15; nb. 16; (2013); p. 4230 - 4233 View in Reaxys

78.4 %

With sodium hydroxide in ethanol, water, Time= 2h, T= 40 °C Umezaki, Satoshi; Yokoshima, Satoshi; Fukuyama, Tohru; Organic Letters; vol. 16; nb. 4; (2014); p. 1269 - 1269 View in Reaxys Umezaki, Satoshi; Yokoshima, Satoshi; Fukuyama, Tohru; Organic Letters; vol. 16; nb. 17; (2014); p. 4692 - 4692 View in Reaxys

54 %

With sodium hydroxide in ethanol, Time= 2h, T= 35 °C , optical yield given as percent ee, enantioselective reaction Inuki, Shinsuke; Iwata, Akira; Oishi, Shinya; Fujii, Nobutaka; Ohno, Hiroaki; Journal of Organic Chemistry; vol.

76; nb. 7; (2011); p. 2072 - 2083 View in Reaxys

O O

OH

O

O

H HO

NH

OH

HN

N

N H

N H

O

S

OH

OH

H

HN

Rx-ID: 23589994 View in Reaxys 2/20 Yield

Conditions & References 2 :Example 2: Preparation of lysergic acid with mother liquor recycling; [0028] Sodium hydroxide (50 grams) was dissolved in water (800 mL) and 200 mL of the concentrated mother liquors from the Example 1. Paspalic acid (100.0 g) (titration assay 98.5percent) and finally sodium hydroxide (150 g) were added to the solution. A two-phase reaction mixture was subsequently formed and was mixed for about 4 hours at about 50°C under nitrogen. The reaction mixture was diluted with water (1000 mL), cooled to 10 °C, and acidified to about pH 3.5 with 40percent sulfuric acid. The obtained suspension was mixed for 2 hours at about 5°C, and the crystalline lysergic acid sulfate was filtered off. The lysergic acid sulfate was extracted with a mixture of methanol and aqueous ammonia 95: 5. (v/v) (3x500 mL). The joined extracts were evaporated to about 200 grams, diluted with water (200 mL), and allowed to crystallize at about 5°C for 24 hours. The crystalline lysergic acid was then separated and washed with water (100 mL) and methanol (3x100 mL). After vacuum drying (24 hours at 60°C and 30 mbar), lysergic acid (90.8 g) was obtained (titration assay 98.7percent, content of paspalic acid 0.6percent, content of isolysergic acid 0.9percent). [0029] The mother liquors after crystallization of lysergic acid and the methanol solution obtained after washing the crystalline product were evaporated to a volume of about 200 mL and were ready to be used in the next batch.

Stage 1: With sodium hydroxide in water, Time= 4h, T= 50 °C Stage 2: With sulfuric acid in water, Time= 2h, T= 5 - 10 °C , pH= ~ 3.5 Patent; IVAX CORPORATION; IVAX PHAMACEUTICALS, S.R.O.; WO2005/82902; (2005); (A1) English View in Reaxys

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O O

N H

O OH

HN N H

N O O

Rx-ID: 31821092 View in Reaxys 3/20 Yield

Conditions & References

52 %

With water, potassium hydroxide in ethanol, Time= 3h, T= 70 °C , Inert atmosphere Liu, Qiang; Jia, Yanxing; Organic Letters; vol. 13; nb. 18; (2011); p. 4810 - 4813 View in Reaxys

52 %

With potassium hydroxide in ethanol, water, Time= 3h, T= 70 °C , Inert atmosphere, enantioselective reaction Liu, Qiang; Zhang, Yu-An; Xu, Ping; Jia, Yanxing; Journal of Organic Chemistry; vol. 78; nb. 21; (2013); p. 10885 - 10893 View in Reaxys

O

OH

O

O

H HO

N

NH

O

H

N

S

OH

OH

H

HN

Rx-ID: 23589993 View in Reaxys 4/20 Yield

Conditions & References 1 :Example 1: Preparation of lysergic acid without mother liquor recycling; [0025] Paspalic acid (100.0 g) (titration assay 98.5percent) was dissolved in 5percent aqueous sodium hydroxide (1000 mL) and then sodium hydroxide (150 g) w as added to the solution. A formation of two-phase mixture was observed. The obtained two-phase mixture was then mixed for about 4 hours at about 50°C under nitrogen. The reaction mixture was diluted with water (1000 mL), cooled to 10°C, and acidified to a pH of about 3.5 with 40percent sulfuric acid. A suspension of crystalline lysergic acid sulfate formed and was mixed for about 2 hours at about 5°C. The crystalline lysergic acid sulfate was filtered off and extracted with a mixture of methanol and aqueous ammonia 95: 5 (v/v) (3x500 mL), and the joined extracts were evaporated to about 200 grams, diluted with water (200 mL), and left to crystallize at about 5°C for 24 hours. The crystalline lysergic acid was then separated and washed with water (100 mL) and methanol (3x100 mL). After vacuum drying (24 hours at 60 °C and 30 mbar), lysergic acid was obtained (73.4 g) (titration assay 99. 1percent, content of paspalic acid 0.5percent, content of isolysergic acid 0.8percent). [0026] The mother liquors after crystallization of lysergic acid and the methanol solution obtained after washing the crystalline product were evaporated to a volume of about 200 mL and were then used in Example 2.

Stage 1: With sodium hydroxide in water, Time= 4h, T= 50 °C Stage 2: With sulfuric acid in water, Time= 2h, T= 5 - 10 °C , pH= ~ 3.5, Product distribution / selectivity Patent; IVAX CORPORATION; IVAX PHAMACEUTICALS, S.R.O.; WO2005/82902; (2005); (A1) English View in Reaxys

O O

NH S

HN O

OH

HN

O

N H

N H

Rx-ID: 10175061 View in Reaxys 5/20 Yield 174 mg

Conditions & References Stage 1: With sodium methylate in methanol, Time= 0.5h, Heating Stage 2: With hydrogenchloride in methanol, Time= 0.75h, Heating Stage 3: With sodium hydroxide in methanol, Time= 0.75h, T= 75 - 80 °C

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Moldvai, Istvan; Temesvari-Major, Eszter; Incze, Maria; Szentirmay, Eva; Gacs-Baitz, Eszter; Szantay, Csaba; Journal of Organic Chemistry; vol. 69; nb. 18; (2004); p. 5993 - 6000 View in Reaxys

NH

O OH

HN

Br

N

O

H

Rx-ID: 12545671 View in Reaxys 6/20 Yield

Conditions & References Reaction Steps: 6 1.1: 55.7 percent / tetrahydrofuran / 24 h / 20 °C 2.1: aq. HCl / 1 h / 37 °C 3.1: 0.758 g / LiBr; TEA / CHCl3 / 12 h / 0 - 5 °C 4.1: (-)-dibenzoyl-L-tartaric acid / acetonitrile; H2O / 60 °C 4.2: 226 mg / NaOH / CHCl3; H2O / pH 9 5.1: 77 percent / tBuOK / tetrahydrofuran; 2-methyl-propan-2-ol / 0.33 h / 0 °C 6.1: aq. HCl / 0.5 h / Heating With hydrogenchloride, TEA, potassium tert-butylate, (-)-Dibenzoyl-L-tartaric acid, lithium bromide in tetrahydrofuran, chloroform, water, acetonitrile, tert-butyl alcohol Moldvai, Istvan; Temesvari-Major, Eszter; Incze, Maria; Szentirmay, Eva; Gacs-Baitz, Eszter; Szantay, Csaba; Journal of Organic Chemistry; vol. 69; nb. 18; (2004); p. 5993 - 6000 View in Reaxys Reaction Steps: 6 1.1: 55.7 percent / tetrahydrofuran / 24 h / 20 °C 2.1: aq. HCl / 1 h / 37 °C 3.1: 0.758 g / LiBr; TEA / CHCl3 / 12 h / 0 - 5 °C 4.1: (-)-dibenzoyl-L-tartaric acid / acetonitrile; H2O / 60 °C 4.2: 226 mg / NaOH / CHCl3; H2O / pH 9 5.1: 77 percent / tBuOK / tetrahydrofuran; 2-methyl-propan-2-ol / 0.33 h / 0 °C 6.1: NaOMe / methanol / 0.5 h / Heating 6.2: HCl / methanol / 0.75 h / Heating 6.3: 174 mg / aq. NaOH / methanol / 0.75 h / 75 - 80 °C With hydrogenchloride, TEA, potassium tert-butylate, sodium methylate, (-)-Dibenzoyl-L-tartaric acid, lithium bromide in tetrahydrofuran, methanol, chloroform, water, acetonitrile, tert-butyl alcohol Moldvai, Istvan; Temesvari-Major, Eszter; Incze, Maria; Szentirmay, Eva; Gacs-Baitz, Eszter; Szantay, Csaba; Journal of Organic Chemistry; vol. 69; nb. 18; (2004); p. 5993 - 6000 View in Reaxys

NH O

O

OH

HN

N O

N H

Rx-ID: 12546405 View in Reaxys 7/20 Yield

Conditions & References Reaction Steps: 4 1.1: 0.758 g / LiBr; TEA / CHCl3 / 12 h / 0 - 5 °C 2.1: (-)-dibenzoyl-L-tartaric acid / acetonitrile; H2O / 60 °C 2.2: 226 mg / NaOH / CHCl3; H2O / pH 9 3.1: 77 percent / tBuOK / tetrahydrofuran; 2-methyl-propan-2-ol / 0.33 h / 0 °C 4.1: aq. HCl / 0.5 h / Heating With hydrogenchloride, TEA, potassium tert-butylate, (-)-Dibenzoyl-L-tartaric acid, lithium bromide in tetrahydrofuran, chloroform, water, acetonitrile, tert-butyl alcohol

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Moldvai, Istvan; Temesvari-Major, Eszter; Incze, Maria; Szentirmay, Eva; Gacs-Baitz, Eszter; Szantay, Csaba; Journal of Organic Chemistry; vol. 69; nb. 18; (2004); p. 5993 - 6000 View in Reaxys Reaction Steps: 4 1.1: 0.758 g / LiBr; TEA / CHCl3 / 12 h / 0 - 5 °C 2.1: (-)-dibenzoyl-L-tartaric acid / acetonitrile; H2O / 60 °C 2.2: 226 mg / NaOH / CHCl3; H2O / pH 9 3.1: 77 percent / tBuOK / tetrahydrofuran; 2-methyl-propan-2-ol / 0.33 h / 0 °C 4.1: NaOMe / methanol / 0.5 h / Heating 4.2: HCl / methanol / 0.75 h / Heating 4.3: 174 mg / aq. NaOH / methanol / 0.75 h / 75 - 80 °C With TEA, potassium tert-butylate, sodium methylate, (-)-Dibenzoyl-L-tartaric acid, lithium bromide in tetrahydrofuran, methanol, chloroform, water, acetonitrile, tert-butyl alcohol Moldvai, Istvan; Temesvari-Major, Eszter; Incze, Maria; Szentirmay, Eva; Gacs-Baitz, Eszter; Szantay, Csaba; Journal of Organic Chemistry; vol. 69; nb. 18; (2004); p. 5993 - 6000 View in Reaxys

NH O

O

OH

HN

N

O

O

N H

Rx-ID: 12547057 View in Reaxys 8/20 Yield

Conditions & References Reaction Steps: 5 1.1: aq. HCl / 1 h / 37 °C 2.1: 0.758 g / LiBr; TEA / CHCl3 / 12 h / 0 - 5 °C 3.1: (-)-dibenzoyl-L-tartaric acid / acetonitrile; H2O / 60 °C 3.2: 226 mg / NaOH / CHCl3; H2O / pH 9 4.1: 77 percent / tBuOK / tetrahydrofuran; 2-methyl-propan-2-ol / 0.33 h / 0 °C 5.1: aq. HCl / 0.5 h / Heating With hydrogenchloride, TEA, potassium tert-butylate, (-)-Dibenzoyl-L-tartaric acid, lithium bromide in tetrahydrofuran, chloroform, water, acetonitrile, tert-butyl alcohol Moldvai, Istvan; Temesvari-Major, Eszter; Incze, Maria; Szentirmay, Eva; Gacs-Baitz, Eszter; Szantay, Csaba; Journal of Organic Chemistry; vol. 69; nb. 18; (2004); p. 5993 - 6000 View in Reaxys Reaction Steps: 5 1.1: aq. HCl / 1 h / 37 °C 2.1: 0.758 g / LiBr; TEA / CHCl3 / 12 h / 0 - 5 °C 3.1: (-)-dibenzoyl-L-tartaric acid / acetonitrile; H2O / 60 °C 3.2: 226 mg / NaOH / CHCl3; H2O / pH 9 4.1: 77 percent / tBuOK / tetrahydrofuran; 2-methyl-propan-2-ol / 0.33 h / 0 °C 5.1: NaOMe / methanol / 0.5 h / Heating 5.2: HCl / methanol / 0.75 h / Heating 5.3: 174 mg / aq. NaOH / methanol / 0.75 h / 75 - 80 °C With hydrogenchloride, TEA, potassium tert-butylate, sodium methylate, (-)-Dibenzoyl-L-tartaric acid, lithium bromide in tetrahydrofuran, methanol, chloroform, water, acetonitrile, tert-butyl alcohol Moldvai, Istvan; Temesvari-Major, Eszter; Incze, Maria; Szentirmay, Eva; Gacs-Baitz, Eszter; Szantay, Csaba; Journal of Organic Chemistry; vol. 69; nb. 18; (2004); p. 5993 - 6000 View in Reaxys

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O

O

N

OH

HN

O

N

N

H

O

O

Rx-ID: 12548056 View in Reaxys 9/20 Yield

Conditions & References Reaction Steps: 6 1.1: 80 percent / methylamine / benzene / 1 h / 10 - 15 °C 2.1: aq. HCl / 1 h / 37 °C 3.1: 0.758 g / LiBr; TEA / CHCl3 / 12 h / 0 - 5 °C 4.1: (-)-dibenzoyl-L-tartaric acid / acetonitrile; H2O / 60 °C 4.2: 226 mg / NaOH / CHCl3; H2O / pH 9 5.1: 77 percent / tBuOK / tetrahydrofuran; 2-methyl-propan-2-ol / 0.33 h / 0 °C 6.1: aq. HCl / 0.5 h / Heating With hydrogenchloride, TEA, potassium tert-butylate, (-)-Dibenzoyl-L-tartaric acid, methylamine, lithium bromide in tetrahydrofuran, chloroform, water, acetonitrile, tert-butyl alcohol, benzene Moldvai, Istvan; Temesvari-Major, Eszter; Incze, Maria; Szentirmay, Eva; Gacs-Baitz, Eszter; Szantay, Csaba; Journal of Organic Chemistry; vol. 69; nb. 18; (2004); p. 5993 - 6000 View in Reaxys Reaction Steps: 6 1.1: 80 percent / methylamine / benzene / 1 h / 10 - 15 °C 2.1: aq. HCl / 1 h / 37 °C 3.1: 0.758 g / LiBr; TEA / CHCl3 / 12 h / 0 - 5 °C 4.1: (-)-dibenzoyl-L-tartaric acid / acetonitrile; H2O / 60 °C 4.2: 226 mg / NaOH / CHCl3; H2O / pH 9 5.1: 77 percent / tBuOK / tetrahydrofuran; 2-methyl-propan-2-ol / 0.33 h / 0 °C 6.1: NaOMe / methanol / 0.5 h / Heating 6.2: HCl / methanol / 0.75 h / Heating 6.3: 174 mg / aq. NaOH / methanol / 0.75 h / 75 - 80 °C With hydrogenchloride, TEA, potassium tert-butylate, sodium methylate, (-)-Dibenzoyl-L-tartaric acid, methylamine, lithium bromide in tetrahydrofuran, methanol, chloroform, water, acetonitrile, tert-butyl alcohol, benzene Moldvai, Istvan; Temesvari-Major, Eszter; Incze, Maria; Szentirmay, Eva; Gacs-Baitz, Eszter; Szantay, Csaba; Journal of Organic Chemistry; vol. 69; nb. 18; (2004); p. 5993 - 6000 View in Reaxys

O O

N HN

OH

HN

H

N H

Rx-ID: 12564480 View in Reaxys 10/20 Yield

Conditions & References Reaction Steps: 2 1: 77 percent / tBuOK / tetrahydrofuran; 2-methyl-propan-2-ol / 0.33 h / 0 °C 2: aq. HCl / 0.5 h / Heating With hydrogenchloride, potassium tert-butylate in tetrahydrofuran, tert-butyl alcohol Moldvai, Istvan; Temesvari-Major, Eszter; Incze, Maria; Szentirmay, Eva; Gacs-Baitz, Eszter; Szantay, Csaba; Journal of Organic Chemistry; vol. 69; nb. 18; (2004); p. 5993 - 6000 View in Reaxys Reaction Steps: 2 1.1: 77 percent / tBuOK / tetrahydrofuran; 2-methyl-propan-2-ol / 0.33 h / 0 °C 2.1: NaOMe / methanol / 0.5 h / Heating

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2.2: HCl / methanol / 0.75 h / Heating 2.3: 174 mg / aq. NaOH / methanol / 0.75 h / 75 - 80 °C With potassium tert-butylate, sodium methylate in tetrahydrofuran, methanol, tert-butyl alcohol Moldvai, Istvan; Temesvari-Major, Eszter; Incze, Maria; Szentirmay, Eva; Gacs-Baitz, Eszter; Szantay, Csaba; Journal of Organic Chemistry; vol. 69; nb. 18; (2004); p. 5993 - 6000 View in Reaxys

O O HN

OH

HN N

N H

Rx-ID: 12567198 View in Reaxys 11/20 Yield

Conditions & References Reaction Steps: 3 1.1: (-)-dibenzoyl-L-tartaric acid / acetonitrile; H2O / 60 °C 1.2: 226 mg / NaOH / CHCl3; H2O / pH 9 2.1: 77 percent / tBuOK / tetrahydrofuran; 2-methyl-propan-2-ol / 0.33 h / 0 °C 3.1: aq. HCl / 0.5 h / Heating With hydrogenchloride, potassium tert-butylate, (-)-Dibenzoyl-L-tartaric acid in tetrahydrofuran, water, acetonitrile, tert-butyl alcohol Moldvai, Istvan; Temesvari-Major, Eszter; Incze, Maria; Szentirmay, Eva; Gacs-Baitz, Eszter; Szantay, Csaba; Journal of Organic Chemistry; vol. 69; nb. 18; (2004); p. 5993 - 6000 View in Reaxys Reaction Steps: 3 1.1: (-)-dibenzoyl-L-tartaric acid / acetonitrile; H2O / 60 °C 1.2: 226 mg / NaOH / CHCl3; H2O / pH 9 2.1: 77 percent / tBuOK / tetrahydrofuran; 2-methyl-propan-2-ol / 0.33 h / 0 °C 3.1: NaOMe / methanol / 0.5 h / Heating 3.2: HCl / methanol / 0.75 h / Heating 3.3: 174 mg / aq. NaOH / methanol / 0.75 h / 75 - 80 °C With potassium tert-butylate, sodium methylate, (-)-Dibenzoyl-L-tartaric acid in tetrahydrofuran, methanol, water, acetonitrile, tert-butyl alcohol Moldvai, Istvan; Temesvari-Major, Eszter; Incze, Maria; Szentirmay, Eva; Gacs-Baitz, Eszter; Szantay, Csaba; Journal of Organic Chemistry; vol. 69; nb. 18; (2004); p. 5993 - 6000 View in Reaxys

O

O

N

OH

HN Br

N H

O

Rx-ID: 12570553 View in Reaxys 12/20 Yield

Conditions & References Reaction Steps: 7 1.1: 35 percent / toluene / 48 h / 20 °C 2.1: 80 percent / methylamine / benzene / 1 h / 10 - 15 °C 3.1: aq. HCl / 1 h / 37 °C 4.1: 0.758 g / LiBr; TEA / CHCl3 / 12 h / 0 - 5 °C 5.1: (-)-dibenzoyl-L-tartaric acid / acetonitrile; H2O / 60 °C 5.2: 226 mg / NaOH / CHCl3; H2O / pH 9 6.1: 77 percent / tBuOK / tetrahydrofuran; 2-methyl-propan-2-ol / 0.33 h / 0 °C 7.1: aq. HCl / 0.5 h / Heating

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With hydrogenchloride, TEA, potassium tert-butylate, (-)-Dibenzoyl-L-tartaric acid, methylamine, lithium bromide in tetrahydrofuran, chloroform, water, toluene, acetonitrile, tert-butyl alcohol, benzene Moldvai, Istvan; Temesvari-Major, Eszter; Incze, Maria; Szentirmay, Eva; Gacs-Baitz, Eszter; Szantay, Csaba; Journal of Organic Chemistry; vol. 69; nb. 18; (2004); p. 5993 - 6000 View in Reaxys Reaction Steps: 7 1.1: 35 percent / toluene / 48 h / 20 °C 2.1: 80 percent / methylamine / benzene / 1 h / 10 - 15 °C 3.1: aq. HCl / 1 h / 37 °C 4.1: 0.758 g / LiBr; TEA / CHCl3 / 12 h / 0 - 5 °C 5.1: (-)-dibenzoyl-L-tartaric acid / acetonitrile; H2O / 60 °C 5.2: 226 mg / NaOH / CHCl3; H2O / pH 9 6.1: 77 percent / tBuOK / tetrahydrofuran; 2-methyl-propan-2-ol / 0.33 h / 0 °C 7.1: NaOMe / methanol / 0.5 h / Heating 7.2: HCl / methanol / 0.75 h / Heating 7.3: 174 mg / aq. NaOH / methanol / 0.75 h / 75 - 80 °C With hydrogenchloride, TEA, potassium tert-butylate, sodium methylate, (-)-Dibenzoyl-L-tartaric acid, methylamine, lithium bromide in tetrahydrofuran, methanol, chloroform, water, toluene, acetonitrile, tert-butyl alcohol, benzene Moldvai, Istvan; Temesvari-Major, Eszter; Incze, Maria; Szentirmay, Eva; Gacs-Baitz, Eszter; Szantay, Csaba; Journal of Organic Chemistry; vol. 69; nb. 18; (2004); p. 5993 - 6000 View in Reaxys

O

OH O

O N H

O

S

OH

O OH

HN

OH

OH

HN

N

N

H

H

HN

Rx-ID: 23589995 View in Reaxys 13/20 Yield

Conditions & References 1; 2 :Example 1: Preparation of lysergic acid without mother liquor recycling; [0025] Paspalic acid (100.0 g) (titration assay 98.5percent) was dissolved in 5percent aqueous sodium hydroxide (1000 mL) and then sodium hydroxide (150 g) w as added to the solution. A formation of two-phase mixture was observed. The obtained two-phase mixture was then mixed for about 4 hours at about 50°C under nitrogen. The reaction mixture was diluted with water (1000 mL), cooled to 10°C, and acidified to a pH of about 3.5 with 40percent sulfuric acid. A suspension of crystalline lysergic acid sulfate formed and was mixed for about 2 hours at about 5°C. The crystalline lysergic acid sulfate was filtered off and extracted with a mixture of methanol and aqueous ammonia 95: 5 (v/v) (3x500 mL), and the joined extracts were evaporated to about 200 grams, diluted with water (200 mL), and left to crystallize at about 5°C for 24 hours. The crystalline lysergic acid was then separated and washed with water (100 mL) and methanol (3x100 mL). After vacuum drying (24 hours at 60 °C and 30 mbar), lysergic acid was obtained (73.4 g) (titration assay 99. 1percent, content of paspalic acid 0.5percent, content of isolysergic acid 0.8percent). [0026] The mother liquors after crystallization of lysergic acid and the methanol solution obtained after washing the crystalline product were evaporated to a volume of about 200 mL and were then used in Example 2.; Example 2: Preparation of lysergic acid with mother liquor recycling; [0028] Sodium hydroxide (50 grams) was dissolved in water (800 mL) and 200 mL of the concentrated mother liquors from the Example 1. Paspalic acid (100.0 g) (titration assay 98.5percent) and finally sodium hydroxide (150 g) were added to the solution. A two-phase reaction mixture was subsequently formed and was mixed for about 4 hours at about 50°C under nitrogen. The reaction mixture was diluted with water (1000 mL), cooled to 10 °C, and acidified to about pH 3.5 with 40percent sulfuric acid. The obtained suspension was mixed for 2 hours at about 5°C, and the crystalline lysergic acid sulfate was filtered off. The lysergic acid sulfate was extracted with a mixture of methanol and aqueous ammonia 95: 5. (v/v) (3x500 mL). The joined extracts were evaporated to about 200 grams, diluted with water (200 mL), and allowed to crystallize at about 5°C for 24 hours. The crystalline lysergic acid was then separated and washed with water (100 mL) and methanol (3x100 mL). After vacuum drying (24 hours at 60°C and 30 mbar), lysergic acid (90.8 g) was obtained (titration assay 98.7percent, content of paspalic acid 0.6percent, content of isolysergic acid 0.9percent). [0029] The mother liquors after crystallization of lysergic acid and the methanol solution obtained after washing the crystalline product were evaporated to a volume of about 200 mL and were ready to be used in the next batch.

With ammonia in methanol, water, Product distribution / selectivity

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Patent; IVAX CORPORATION; IVAX PHAMACEUTICALS, S.R.O.; WO2005/82902; (2005); (A1) English View in Reaxys

O

ergine

OH

HN N H

Rx-ID: 5714716 View in Reaxys 14/20 Yield

Conditions & References With sodium hydroxide Acramone et al.; ; vol. 155; (1961); p. 26,49 View in Reaxys Smith; Timmis; Journal of the Chemical Society; (1934); p. 674; Journal of the Chemical Society; (1936); p. 1440,1443 View in Reaxys With potassium hydroxide Acramone et al.; ; vol. 155; (1961); p. 26,49 View in Reaxys Smith; Timmis; Journal of the Chemical Society; (1934); p. 674; Journal of the Chemical Society; (1936); p. 1440,1443 View in Reaxys

O O

NH S

HN O

O OH

HN

OH

HN

O N

N

N

H

H

H

Rx-ID: 10175060 View in Reaxys 15/20 Yield

Conditions & References With hydrogenchloride, Time= 0.5h, Heating, Title compound not separated from byproducts Moldvai, Istvan; Temesvari-Major, Eszter; Incze, Maria; Szentirmay, Eva; Gacs-Baitz, Eszter; Szantay, Csaba; Journal of Organic Chemistry; vol. 69; nb. 18; (2004); p. 5993 - 6000 View in Reaxys

O

HO H N

H H

O OH

HN N

N

H

H

HN

Rx-ID: 858173 View in Reaxys 16/20 Yield

Conditions & References With potassium hydroxide Stoll; Hofmann; Hoppe-Seyler's Zeitschrift fuer Physiologische Chemie; vol. 250; (1937); p. 7,9 View in Reaxys Stoll; Hofmann; Helvetica Chimica Acta; vol. 26; (1943); p. 922,925 View in Reaxys

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O O

O

O

O

O

HN

S

OH

HN

F

N

N

O

H

Rx-ID: 1618910 View in Reaxys 17/20 Yield

Conditions & References Yield given. Multistep reaction Oppolzer, Wolfgang; Francotte, Eric; Baettig, Kurt; Helvetica Chimica Acta; vol. 64; nb. 2; (1981); p. 478 - 481 View in Reaxys

O H

H O

OH

HN

KO H

O OH

HN

N

N

H

H

Rx-ID: 5714717 View in Reaxys 18/20 Yield

Conditions & References Smith; Timmis; Journal of the Chemical Society; (1936); p. 1440 View in Reaxys

O OH

HN N H

Rx-ID: 5714715 View in Reaxys 19/20 Yield

Conditions & References Ergotoxin Chilton,J.; Stenlake,J.B.; Journal of Pharmacy and Pharmacology; vol. 14; (1962); p. 367 - 370 View in Reaxys Elymoclavin (6), Cyclohexanon, Al(O-t-Bu)3 Mayer; Eich; Archiv der Pharmazie (Weinheim, Germany); vol. 308; (1975); p. 819,823 View in Reaxys 2 : EXAMPLE 2 EXAMPLE 2 130 g of paspalic acid are added rapidly to 472.3 g of a 40percent strength solution of tetrabutylammonium hydroxide in water, with stirring and under a stream of nitrogen, followed by 316 g of a 1.5N aqueous solution of sodium hydroxide.

The mixture is brought to 30+-2° C. and allowed to react at this temperature for 20 hours.

The reaction medium is cooled to about 20° C. and held at this temperature for 3 h 30 min. 918 g of water are added, followed by acidification using 95percent strength sulphuric acid until the pH is 3.5, while maintaining the temperature at about 30° C. The reaction mixture is then cooled to 10+-2° C. and held at this temperature for 30 minutes.

The mixture is filtered through a sinter funnel under a vacuum of 0.4 bar, washed 3 times with 300 ml of water and then dried for 14 hours at 75+-2° C. and 20 mbar.

This gives 107.8 g of lysergic acid comprising only 2.8percent of isolysergic acid and the RRi is 81.6percent.

Patent; Aventis Pharma S.A.; US6242603; (2001); (B1) English View in Reaxys A-Preparation of Lysergic Acid with Sodium Hydroxide Alone A-Preparation of Lysergic Acid with Sodium Hydroxide Alone 5 g of paspalic acid in 100 ml of a 2N aqueous solution of sodium hydroxide are heated at reflux for 2 hours.

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After cooling, the pH of the reaction medium is brought to 5.5 by adding an aqueous solution of hydrochloric acid and glacial acetic acid (20 ml of water, 10 ml of hydrochloric acid and 10 ml of acetic acid).

The precipitate is filtered, washed with 3 times 20 ml of a water/methanol (50:50) mixture, then dried in vacuo at 75° C. This gives 3.15 g of lysergic acid comprising 6.8percent of isolysergic acid and the RRi is 59.3percent.

Patent; Aventis Pharma S.A.; US6242603; (2001); (B1) English View in Reaxys B-Preparation of Lysergic Acid with Potassium Hydroxide Alone 5 g of paspalic acid in 360 g of a 0.5N solution of potassium hydroxide in a water/ethanol (50:50) mixture are heated at reflux for 1 hour.

After cooling, the pH of the reaction medium is brought to 5.5 by adding 1N hydrochloric acid.

The precipitate is filtered, washed with 3 times 20 ml of a water/methanol (50:50) mixture, then dried in vacuo at 75° C. This gives 2.86 g of lysergic acid comprising 1percent of isolysergic acid and the RRi is 49.8percent.

Patent; Aventis Pharma S.A.; US6242603; (2001); (B1) English View in Reaxys

O

OH

H N 14CH

2

HN

Rx-ID: 6009425 View in Reaxys 20/20 Yield

Conditions & References 11d (Umlager.)

Schreier; Helvetica Chimica Acta; vol. 59; (1976); p. 585,588, 597 View in Reaxys 1d, Claviceps paspali Schreier; Helvetica Chimica Acta; vol. 59; (1976); p. 585,588, 597 View in Reaxys

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