1200-22-2

Basic information

• Product Name: (R)-(+)-1,2-Dithiolane-3-pentanoic acid
• Synonyms: 5-[(3R)-1,2-dithiolan-3-yl]pentanoic acid;5-[(3R)-dithiolan-3-yl]pentanoic acid;5-[(3R)-dithiolan-3-yl]valeric acid;(R)-(+)-1,2-Dithiola;(R)-5-(1,2-Dithiolan-3-yl)pentanoic acid;(R)-Thioctic Acid (R)-1,2-Dithiolane-3-valeric Acid;D-lipoic acid;(R)-(+)-1,2-Dithiolane-3-pentanoic acid 97%
• CAS NO: 1200-22-2
• Molecular Formula: C₈H₁₄O₂S₂
• Molecular Weight: 206.33
• EINECS: 1308068-626-2
• Product Categories: Sulfur & Selenium Compounds;Chiral Building Blocks;Heterocyclic Building Blocks;Others;API;FINE Chemical & INTERMEDIATES;Chiral Reagents;Heterocycles
• Mol File: 1200-22-2.mol
• Article Data: 49

Chemical Properties

• Melting Point: 48-52 °C(lit.)
• Boiling Point: 362.5 °C at 760 mmHg
• Flash Point: >230 °F
• Appearance: yellow crystalline solid
• Density: 1.218 g/cm³
• Refractive Index: 114 ° (C=1, EtOH)
• Storage Temp.: -20°C Freezer
• Solubility: Acetonitrile (Slightly), Chloroform (Slightly), DMSO
• PKA: 5.4(at 25℃)
• Merck: 14,9326
• CAS DataBase Reference: (R)-(+)-1,2-Dithiolane-3-pentanoic acid(CAS DataBase Reference)
• NIST Chemistry Reference: (R)-(+)-1,2-Dithiolane-3-pentanoic acid(1200-22-2)
• EPA Substance Registry System: (R)-(+)-1,2-Dithiolane-3-pentanoic acid(1200-22-2)

Safety Data

• Statements: 22-36/38
• Safety Statements: 20-36-26-35
• WGK Germany: 3
• Hazardous Substances Data: 1200-22-2(Hazardous Substances Data)

Usage

Chemical Properties

Yellow Crystalline Solid

Uses

α-Lipoic acid has been used as a reference standard for the analysis of α-lipoic acid in human plasma by high performance liquid chromatography coupled to electron capture detector (HPLC-ECD), in various food matrices and dietary supplements by HPLC combined with coulometric electrode array detector (CEAD) as well as electrospray ionization mass spectrometer (ESI-MS). It may be used as a reference standard for the determination of α-lipoic acid in human urine by isocratic reversed-phase HPLC and in α-lipoic acid capsules by HPLC with chemiluminescence detection.

General Description

α-Lipoic acid is an antioxidant which is generally present in plants, animals and many other microorganisms.

Biochem/physiol Actions

(R)-(+)-α-Lipoic acid was shown to significantly increase pyruvate oxidation while abrogating fatty acid oxidation in rat hepatocytes. These effects make R-(+)-α-Lipoic acid a promising treatment option for the treatment of Type II diabetes. It is a biological antioxidant with prooxidant activities, its therapeutic potential is widely investigated, e.g. in the treatment for Alzheimer′s disease.

InChI:InChI=1/C8H14O2S2/c9-8(10)4-2-1-3-7-5-6-11-12-7/h7H,1-6H2,(H,9,10)/t7-/m1/s1

Synthetic route

(S)-6,8-dichlorooctanoic acid ethylester → (R)-1,2-dithiolane-3-pentanoic acid (1200-22-2)

Conditions	Yield
Stage #1: (S)-6,8-dichlorooctanoic acid ethylester With sodium sulfide; sulfur In water at 80℃; for 2h; Stage #2: With water; sodium hydroxide at 80℃; for 8h; Temperature;	99.8%
With sodium sulfide; sulfur
Stage #1: (S)-6,8-dichlorooctanoic acid ethylester With sodium sulfide; sulfur In water at 82℃; for 4.5h; Stage #2: With water; sodium hydroxide In toluene at 92℃; for 8h; pH=1; Solvent; Temperature;	n/a

(+)-isopropyl lipoate (97961-65-4) → (R)-1,2-dithiolane-3-pentanoic acid (1200-22-2)

Conditions	Yield
With water; potassium carbonate In methanol at 22℃; for 40h;	96%

(R)-6,8-dichloroctanoic acid (188412-21-7) → (R)-1,2-dithiolane-3-pentanoic acid (1200-22-2)

Conditions	Yield
With sodium sulfide; N-benzyl-N,N,N-triethylammonium chloride; sulfur In water at 85℃; Reagent/catalyst; Temperature;	92.1%

C8H14O2S2*C7H9NO → (R)-1,2-dithiolane-3-pentanoic acid (1200-22-2)

Conditions	Yield
With citric acid In methanol; toluene at 35 - 40℃; for 3h; Temperature; Darkness; Industrial scale;	83.1%

[ethyl (5R)-5-(1,2-dithiolan-3yl)pentanoate] (104726-74-1) → (R)-1,2-dithiolane-3-pentanoic acid (1200-22-2)

Conditions	Yield
With hydrogenchloride; potassium hydroxide In ethanol for 24h; Ambient temperature;	75%
With potassium hydroxide In ethanol at 20℃; for 24h;	75%
With potassium hydroxide In ethanol at 20℃; for 24h;	75%
hydrolysis;
With sodium hydroxide

(+)-6,8-dichlorooctanoic acid → (R)-1,2-dithiolane-3-pentanoic acid (1200-22-2)

Conditions	Yield
Product distribution / selectivity;	72%

(R)-5-[1,2-dithiolan-3-yl]pentanoic acid methyl ester (99427-00-6) → (R)-1,2-dithiolane-3-pentanoic acid (1200-22-2)

Conditions	Yield
With potassium hydroxide In methanol for 3h; Ambient temperature;	70%
With potassium hydroxide; water for 24h;	54%
Stage #1: (R)-5-[1,2-dithiolan-3-yl]pentanoic acid methyl ester With potassium hydroxide In methanol; water at 50℃; for 2h; Stage #2: With phosphoric acid In methanol; water; toluene at 30℃;	45%
With potassium carbonate In methanol; water

Potassium; (S)-6,8-bis-methanesulfonyloxy-octanoate → (R)-1,2-dithiolane-3-pentanoic acid (1200-22-2)

Conditions	Yield
	52%

C8H11N*C8H14O2S2 → (R)-1,2-dithiolane-3-pentanoic acid (1200-22-2) + (S)-lipoic acid (62-46-4, 1077-27-6, 1077-28-7, 1200-22-2, 52578-51-5)

Conditions	Yield
With sulfuric acid In acetone at 15 - 60℃; for 2h; Temperature; Solvent;	A 47.5% B n/a

C8H11N*C8H14O2S2 → (R)-1,2-dithiolane-3-pentanoic acid (1200-22-2)

Conditions	Yield
With sulfuric acid In acetone at 15 - 40℃; for 24h; Solvent;	46%

(S)-6,8-dimethylsulfonyloxyoctane-1-carboxylic acid (107554-84-7) → (R)-1,2-dithiolane-3-pentanoic acid (1200-22-2) + (S)-lipoic acid (62-46-4, 1077-27-6, 1077-28-7, 1200-22-2, 52578-51-5)

Conditions	Yield
With hydrogenchloride; sodium sulfide; potassium hydroxide In water; N,N-dimethyl-formamide at 80℃; for 28h; Title compound not separated from byproducts;	A n/a B 45%

6,8-dichlorooctanoic acid ethyl ester (1070-64-0) → (R)-1,2-dithiolane-3-pentanoic acid (1200-22-2)

Conditions	Yield
With ammonium hydrogen sulfite; sodium sulfide nonahydrate; sulfur In propan-1-ol; water; isopropyl alcohol at 70℃; for 3.5h; Temperature; Solvent; Reagent/catalyst; Inert atmosphere; Darkness;	30.6%

Thioctic acid (1077-28-7, 62-46-4) → (R)-1,2-dithiolane-3-pentanoic acid (1200-22-2)

Conditions	Yield
With cinchonidine salt

(R)-6,8-dimercaptooctanoic acid (119365-69-4) → (R)-1,2-dithiolane-3-pentanoic acid (1200-22-2)

Conditions	Yield
With iron(III) chloride; potassium carbonate
With chloroform; iodine; potassium iodide
With mushroom tyrosinase

(S)-6,8-dimethylsulfonyloxyoctane-1-carboxylic acid (107554-84-7) → (R)-1,2-dithiolane-3-pentanoic acid (1200-22-2)

Conditions	Yield
With sodium sulfide; potassium hydroxide; sulfur 1.) 5 min, 2.) DMF, 80 deg C, 24h; Yield given. Multistep reaction;

(7R,10S)-7-Isopropyl-10-methyl-1,5-dithia-spiro[5.5]undecane (114529-48-5) → l-menthone (3391-87-5) + (R)-1,2-dithiolane-3-pentanoic acid (1200-22-2)

Conditions	Yield
Multistep reaction;

(3S)-6-bromo-1,3-isopropylidendioxyhexane (139685-60-2) → (R)-1,2-dithiolane-3-pentanoic acid (1200-22-2)

1,2-dithiolane-3-pentanoic acid methyl ester (46236-19-5) → (R)-1,2-dithiolane-3-pentanoic acid (1200-22-2) + (S)-lipoic acid (62-46-4, 1077-27-6, 1077-28-7, 1200-22-2, 52578-51-5)

Conditions	Yield
With potassium hydroxide In methanol Yield given. Title compound not separated from byproducts;

sodium-salt of/the/ (+)-6,8-dichloro-octanoic acid → (R)-1,2-dithiolane-3-pentanoic acid (1200-22-2)

Conditions	Yield
With ethanol; sodium disulfide

(6S)-(-)-methyl 6,8-dihydroxyoctanoate (116349-04-3) → (R)-1,2-dithiolane-3-pentanoic acid (1200-22-2)

Conditions	Yield
Multi-step reaction with 3 steps 1: Et3N / CH2Cl2 2: Na2S; sulphur / dimethylformamide / 24 h / 90 °C 3: K2CO3 / methanol; H2O View Scheme
Multi-step reaction with 4 steps 1: Et3N / CH2Cl2 / 1 h / 0 °C 2: dimethylformamide; cyclohexane / 4 h / 50 °C 3: H2O; KOH / 6 h / 20 °C 4: FeCl3; air; NaOH / H2O / 3 h / pH 9 View Scheme
Multi-step reaction with 3 steps 1: 92 percent / Et3N / CH2Cl2 / 0.5 h / 0 °C 2: 83 percent / Na2S*9H2O, sulfur / dimethylformamide / 2.42 h / 80 °C 3: 70 percent / aq. KOH / methanol / 3 h / Ambient temperature View Scheme
Multi-step reaction with 3 steps 1: 98 percent / Et3N 2: 1.) sodium sulphide nonahydrate, sulphur / 1.) DMF, 80 deg C, 1 h, 2.)DMF, 80 deg C, 67 h, then RT, 17 h 3: 54 percent / 0.1M KOH, H2O / 24 h View Scheme

(S)-6,8-diphenylmethoxyoctanoic acid (116315-78-7) → (R)-1,2-dithiolane-3-pentanoic acid (1200-22-2)

Conditions	Yield
Multi-step reaction with 5 steps 1: 1.75 g / diethyl ether 2: 87 percent / H2 / Pd/C / ethanol / 5 h / 2585.81 Torr 3: Et3N / CH2Cl2 4: Na2S; sulphur / dimethylformamide / 24 h / 90 °C 5: K2CO3 / methanol; H2O View Scheme
Multi-step reaction with 5 steps 1: 3percent HCl 2: 95 percent / H2 / 5percent palladium on charcoal / methanol / 1551.4 Torr 3: 98 percent / Et3N 4: 1.) sodium sulphide nonahydrate, sulphur / 1.) DMF, 80 deg C, 1 h, 2.)DMF, 80 deg C, 67 h, then RT, 17 h 5: 54 percent / 0.1M KOH, H2O / 24 h View Scheme

(6S)-(+)-methyl 6,8-bis(methylsulfonyloxy)octanoate (116349-05-4) → (R)-1,2-dithiolane-3-pentanoic acid (1200-22-2)

Conditions	Yield
Multi-step reaction with 2 steps 1: Na2S; sulphur / dimethylformamide / 24 h / 90 °C 2: K2CO3 / methanol; H2O View Scheme
Multi-step reaction with 3 steps 1: dimethylformamide; cyclohexane / 4 h / 50 °C 2: H2O; KOH / 6 h / 20 °C 3: FeCl3; air; NaOH / H2O / 3 h / pH 9 View Scheme
Multi-step reaction with 2 steps 1: 83 percent / Na2S*9H2O, sulfur / dimethylformamide / 2.42 h / 80 °C 2: 70 percent / aq. KOH / methanol / 3 h / Ambient temperature View Scheme
Multi-step reaction with 2 steps 1: 1.) sodium sulphide nonahydrate, sulphur / 1.) DMF, 80 deg C, 1 h, 2.)DMF, 80 deg C, 67 h, then RT, 17 h 2: 54 percent / 0.1M KOH, H2O / 24 h View Scheme

(S)-1-phenylmethoxyoct-7-en-3-ol (116315-75-4) → (R)-1,2-dithiolane-3-pentanoic acid (1200-22-2)

Conditions	Yield
Multi-step reaction with 8 steps 1.1: 85 percent / TBAI; NaH / dimethylformamide / 2 h / 20 °C 2.1: BH3*DMS / tetrahydrofuran / 2 h / 20 °C 2.2: 88 percent / aq. NaOEt; H2O2 / tetrahydrofuran / 2 h / 20 °C 3.1: aq. NaCl2O; NaOCl; TEMPO / acetonitrile; aq. phosphate buffer / 35 °C / pH 6.7 4.1: 1.75 g / diethyl ether 5.1: 87 percent / H2 / Pd/C / ethanol / 5 h / 2585.81 Torr 6.1: Et3N / CH2Cl2 7.1: Na2S; sulphur / dimethylformamide / 24 h / 90 °C 8.1: K2CO3 / methanol; H2O View Scheme
Multi-step reaction with 8 steps 1: 95 percent 2: 89 percent / diisopentylborane / tetrahydrofuran / 0 °C 3: pyridinium dichromate / dimethylformamide / 0 deg C, then RT, 24 h 4: 3percent HCl 5: 95 percent / H2 / 5percent palladium on charcoal / methanol / 1551.4 Torr 6: 98 percent / Et3N 7: 1.) sodium sulphide nonahydrate, sulphur / 1.) DMF, 80 deg C, 1 h, 2.)DMF, 80 deg C, 67 h, then RT, 17 h 8: 54 percent / 0.1M KOH, H2O / 24 h View Scheme

(S)-6,8-diphenylmethoxyoct-1-ene (116315-76-5) → (R)-1,2-dithiolane-3-pentanoic acid (1200-22-2)

Conditions	Yield
Multi-step reaction with 7 steps 1.1: BH3*DMS / tetrahydrofuran / 2 h / 20 °C 1.2: 88 percent / aq. NaOEt; H2O2 / tetrahydrofuran / 2 h / 20 °C 2.1: aq. NaCl2O; NaOCl; TEMPO / acetonitrile; aq. phosphate buffer / 35 °C / pH 6.7 3.1: 1.75 g / diethyl ether 4.1: 87 percent / H2 / Pd/C / ethanol / 5 h / 2585.81 Torr 5.1: Et3N / CH2Cl2 6.1: Na2S; sulphur / dimethylformamide / 24 h / 90 °C 7.1: K2CO3 / methanol; H2O View Scheme
Multi-step reaction with 7 steps 1: 89 percent / diisopentylborane / tetrahydrofuran / 0 °C 2: pyridinium dichromate / dimethylformamide / 0 deg C, then RT, 24 h 3: 3percent HCl 4: 95 percent / H2 / 5percent palladium on charcoal / methanol / 1551.4 Torr 5: 98 percent / Et3N 6: 1.) sodium sulphide nonahydrate, sulphur / 1.) DMF, 80 deg C, 1 h, 2.)DMF, 80 deg C, 67 h, then RT, 17 h 7: 54 percent / 0.1M KOH, H2O / 24 h View Scheme

(S)-6,8-diphenylmethoxyoctan-1-ol (116315-77-6) → (R)-1,2-dithiolane-3-pentanoic acid (1200-22-2)

Conditions	Yield
Multi-step reaction with 6 steps 1: aq. NaCl2O; NaOCl; TEMPO / acetonitrile; aq. phosphate buffer / 35 °C / pH 6.7 2: 1.75 g / diethyl ether 3: 87 percent / H2 / Pd/C / ethanol / 5 h / 2585.81 Torr 4: Et3N / CH2Cl2 5: Na2S; sulphur / dimethylformamide / 24 h / 90 °C 6: K2CO3 / methanol; H2O View Scheme
Multi-step reaction with 6 steps 1: pyridinium dichromate / dimethylformamide / 0 deg C, then RT, 24 h 2: 3percent HCl 3: 95 percent / H2 / 5percent palladium on charcoal / methanol / 1551.4 Torr 4: 98 percent / Et3N 5: 1.) sodium sulphide nonahydrate, sulphur / 1.) DMF, 80 deg C, 1 h, 2.)DMF, 80 deg C, 67 h, then RT, 17 h 6: 54 percent / 0.1M KOH, H2O / 24 h View Scheme

(S)-methyl 6,8-diphenylmethoxyoctanoate (116315-79-8) → (R)-1,2-dithiolane-3-pentanoic acid (1200-22-2)

Conditions	Yield
Multi-step reaction with 4 steps 1: 87 percent / H2 / Pd/C / ethanol / 5 h / 2585.81 Torr 2: Et3N / CH2Cl2 3: Na2S; sulphur / dimethylformamide / 24 h / 90 °C 4: K2CO3 / methanol; H2O View Scheme
Multi-step reaction with 4 steps 1: 95 percent / H2 / 5percent palladium on charcoal / methanol / 1551.4 Torr 2: 98 percent / Et3N 3: 1.) sodium sulphide nonahydrate, sulphur / 1.) DMF, 80 deg C, 1 h, 2.)DMF, 80 deg C, 67 h, then RT, 17 h 4: 54 percent / 0.1M KOH, H2O / 24 h View Scheme

ethyl (S)-6,8-dihydroxy octanoate (104726-72-9) → (R)-1,2-dithiolane-3-pentanoic acid (1200-22-2)

Conditions	Yield
Multi-step reaction with 3 steps 1: 92 percent / Et3N / CH2Cl2 / 4 h / 0 °C 2: 72 percent / Na2S; S / dimethylformamide / 24 h / 90 °C 3: 75 percent / KOH / ethanol / 24 h / 20 °C View Scheme
Multi-step reaction with 3 steps 1: Et3N / CH2Cl2 / 4 h / 0 °C 2: 70 percent / sodium sulfide nonahydrate, sulfur / dimethylformamide / 24 h / 90 °C 3: 75 percent / 1.) 0.1M potassium hydroxide, 2.) 5M HCl / ethanol / 24 h / Ambient temperature View Scheme
Multi-step reaction with 3 steps 2: Na2S - S / dimethylformamide / 90 °C 3: hydrolysis View Scheme
Multi-step reaction with 3 steps 1: triethylamine / dichloromethane / 4 h / 0 °C 2: sodiumsulfide nonahydrate; sulfur / N,N-dimethyl-formamide / 24 h / 85 - 90 °C 3: potassium hydroxide / ethanol / 24 h / 20 °C View Scheme

(S)-Ethyl 6,8-Bis(methylsulphonyloxy)octanoate (104726-73-0) → (R)-1,2-dithiolane-3-pentanoic acid (1200-22-2)

Conditions	Yield
Multi-step reaction with 2 steps 1: 72 percent / Na2S; S / dimethylformamide / 24 h / 90 °C 2: 75 percent / KOH / ethanol / 24 h / 20 °C View Scheme
Multi-step reaction with 2 steps 1: 70 percent / sodium sulfide nonahydrate, sulfur / dimethylformamide / 24 h / 90 °C 2: 75 percent / 1.) 0.1M potassium hydroxide, 2.) 5M HCl / ethanol / 24 h / Ambient temperature View Scheme
Multi-step reaction with 2 steps 1: Na2S - S / dimethylformamide / 90 °C 2: hydrolysis View Scheme
Multi-step reaction with 2 steps 1: sodiumsulfide nonahydrate; sulfur / N,N-dimethyl-formamide / 24 h / 85 - 90 °C 2: potassium hydroxide / ethanol / 24 h / 20 °C View Scheme

(R)-1,2-dithiolane-3-pentanoic acid (1200-22-2) → (R)-6,8-dimercaptooctanoic acid (119365-69-4)

Conditions	Yield
With sodium tetrahydroborate In methanol at 20℃; for 1h;	100%
With 1,4-dihydronicotinamide adenine dinucleotide; porcine heart dihydrolipoamide dehydrogenase at 35℃; Enzyme kinetics;
With sodium borohydrid In water; toluene

dimethylbiguanide (657-24-9) + (R)-1,2-dithiolane-3-pentanoic acid (1200-22-2) → N,N-dimethylimidodicarbonimidic diamide R-(+)-lipoate (959986-37-9)

Conditions	Yield
In methanol for 2h; Product distribution / selectivity;	100%
In acetonitrile for 0.166667h; Product distribution / selectivity;	95%
In acetone for 0.166667 - 0.5h; Product distribution / selectivity;	95%
In methanol; acetone for 0.333333h; Product distribution / selectivity;

pyridoxamine (85-87-0) + (R)-1,2-dithiolane-3-pentanoic acid (1200-22-2) → (3-hydroxy-5-(hydroxymethyl)-2-methylpyridin-4-yl)methanaminium (R)-5-( 1,2-dithiolan-3-yl)pentanoate

Conditions	Yield
In tetrahydrofuran at 20℃; for 2h;	100%
In ethanol at 20 - 50℃; for 0.5h;	68%

(R)-1,2-dithiolane-3-pentanoic acid (1200-22-2) → dihydrolipoic acid (462-20-4)

Conditions	Yield
With hydrogenchloride; sodium borohydrid; sodium hydrogencarbonate In water	100%
With sodium tetrahydroborate; sodium hydrogencarbonate In water at 5 - 20℃; for 1.25h;	96.8 mg

Duloxetine (116539-58-3, 116539-59-4, 116539-60-7, 116817-13-1) + (R)-1,2-dithiolane-3-pentanoic acid (1200-22-2) → (S)-N-methyl-3-(naphthalen-1-yloxy)-3-(thiophen-2-yl)propan-1-aminium (R)-5-(1,2-dithiolan-3-yl)pentanoate

Conditions	Yield
In tetrahydrofuran for 2h;	100%

tropicamide (1508-75-4) + (R)-1,2-dithiolane-3-pentanoic acid (1200-22-2) → (R)-5-(1,2-dithiolan-3-yl)pentanoic acid N-ethyl-3-hydroxy-2-phenyl-N-(pyridin-4-ylmethyl)propanamide

Conditions	Yield
In dichloromethane at 20℃; for 4h;	100%

tetrahydrozoline (84-22-0) + (R)-1,2-dithiolane-3-pentanoic acid (1200-22-2) → (R)-5-(1,2-dithiolan-3-yl)pentanoate 2-(1,2,3,4-tetrahydronaphthalen-1-yl)-4,5-dihydro-1H-imidazol-1-ium

Conditions	Yield
In dichloromethane at 20℃; for 4h;	100%

2-amino-2-hydroxymethyl-1,3-propanediol (77-86-1) + (R)-1,2-dithiolane-3-pentanoic acid (1200-22-2) → R-lipoic acid tromethamine salt

Conditions	Yield
With ethyl acetate at 40℃; for 4h;	99.64%

(R)-1,2-dithiolane-3-pentanoic acid (1200-22-2) → magnesium R-(+)-α-lipoate

Conditions	Yield
With dihydro-(+)-lipoic acid; magnesium methanolate In isopropyl alcohol at 15 - 20℃; for 0.35h; Product distribution / selectivity;	98.7%
With magnesium hydroxide In ethanol	85%
With magnesium methanolate In methanol; isopropyl alcohol Inert atmosphere;

bethanechol chloride (590-63-6) + (R)-1,2-dithiolane-3-pentanoic acid (1200-22-2) → 2-(carbamoyloxy)-N,N,N-trimethylpropan-1-aminium (R)-5-(1,2-dithiolan-3-yl)pentanoate

Conditions	Yield
Stage #1: bethanechol chloride With sodium hydrogencarbonate In methanol at 20℃; for 0.0833333h; Stage #2: (R)-1,2-dithiolane-3-pentanoic acid In methanol at 20℃; for 16h;	97.6%

3β-hydroxyoleanane-12-en-28-oic acid(6-bromohexyl) ester (1161826-45-4) + (R)-1,2-dithiolane-3-pentanoic acid (1200-22-2) → [((5-((R)-1,2-dithiolan-3-yl)pentanoyl)oxy)hexyl]-3β-hydroxyolean-12-en-28-oate

Conditions	Yield
With potassium carbonate In N,N-dimethyl-formamide at 50℃; for 24h;	96%

(R)-1,2-dithiolane-3-pentanoic acid (1200-22-2) → sodium lipoic acid

Conditions	Yield
With sodium ethanolate In ethanol	95%

2-(N,N-dimethylamino)ethanol (108-01-0) + (R)-1,2-dithiolane-3-pentanoic acid (1200-22-2) → R-(+)-LA dimethylethanolamine salt (919507-94-1)

Conditions	Yield
In ethanol	95%

methanol (67-56-1) + (R)-1,2-dithiolane-3-pentanoic acid (1200-22-2) → (R)-5-[1,2-dithiolan-3-yl]pentanoic acid methyl ester (99427-00-6)

Conditions	Yield
With sulfuric acid at 78.3℃; for 1h; Dean-Stark;	95%
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 20℃; for 5h;
With thionyl chloride at 0 - 20℃; for 1h;
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; Cooling with ice;

2,3,4,5,6-pentafluorophenol (771-61-9) + (R)-1,2-dithiolane-3-pentanoic acid (1200-22-2) → (R)-perfluorophenyl 5-(1,2-dithiolan-3-yl)pentanoate

Conditions	Yield
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 25℃; for 19h;	95%
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N,N-dimethyl-formamide In dichloromethane at 20℃;	94%
With dicyclohexyl-carbodiimide In 1,4-dioxane at 0 - 20℃;

Taurine + (R)-1,2-dithiolane-3-pentanoic acid (1200-22-2) → N-[(R)-1,2-dithiolane-3-pentanoyl]taurine (874111-37-2)

Conditions	Yield
Stage #1: (R)-1,2-dithiolane-3-pentanoic acid With di(succinimido) carbonate; N-ethyl-N,N-diisopropylamine In acetone at 20℃; for 2h; Darkness; Stage #2: Taurine With water; N-ethyl-N,N-diisopropylamine In acetone	95%

choline bromide (1927-06-6) + (R)-1,2-dithiolane-3-pentanoic acid (1200-22-2) → R-lipoic acid choline ester bromide

Conditions	Yield
With 2,6-dimethylpyridine; 1,1'-carbonyldiimidazole In 1,2-dichloro-ethane at 20℃; for 24h; Cooling with ice; Green chemistry;	95%
With 2,6-dimethylpyridine; 1,1'-carbonyldiimidazole In chloroform at 20℃; for 24h; Solvent; Reagent/catalyst; Temperature;	85%

(2S,4R)-1-(6-aminohexanoyl)-4-hydroxy-2-(4,4′-dimethoxytrityloxymethyl)pyrrolidine (851912-61-3) + (R)-1,2-dithiolane-3-pentanoic acid (1200-22-2) → (2S,4R)-4-hydroxy-2-(4,4'-dimethoxytrityloxymethyl)-1-(6-(N-(5-((R)-1,2-dithiolan-3-yl)pentanoylamino)hexanoyl))pyrrolidine

Conditions	Yield
Stage #1: (R)-1,2-dithiolane-3-pentanoic acid With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide for 0.166667h; Stage #2: (2S,4R)-1-(6-aminohexanoyl)-4-hydroxy-2-(4,4′-dimethoxytrityloxymethyl)pyrrolidine In N,N-dimethyl-formamide at 25℃; for 1h;	95%

piperazine (110-85-0) + (R)-1,2-dithiolane-3-pentanoic acid (1200-22-2) → piperazine di-(R)-α-lipoate

Conditions	Yield
In acetone at 20℃; for 4h; Product distribution / selectivity; Reflux;	94.5%
In acetone at 0 - 15℃; for 3h;	92.3%
In acetone at 0 - 15℃; for 3h;	92.3%
In acetone at 0 - 15℃; for 3h;	92.3%

1-hydroxy-pyrrolidine-2,5-dione (6066-82-6) + (R)-1,2-dithiolane-3-pentanoic acid (1200-22-2) → 2,5-dioxopyrrolidin-1-yl 5-(1,2-dithiolan-3-yl)pentanoate (1115175-97-7)

Conditions	Yield
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃;	94%
With dicyclohexyl-carbodiimide In tetrahydrofuran; dichloromethane at 4 - 20℃; for 5h;	75.8%
With dicyclohexyl-carbodiimide In dichloromethane at 0 - 20℃; for 16h;	66%
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane Inert atmosphere;

bromohexyl-3β-hydroxy-urs-12-en-28-oate (1383539-92-1) + (R)-1,2-dithiolane-3-pentanoic acid (1200-22-2) → [((5-((R)-1,2-dithiolan-3-yl)pentanoyl)oxy)hexyl]-3β-hydroxyurs-12-en-28-oate

Conditions	Yield
With potassium carbonate In N,N-dimethyl-formamide at 50℃; for 24h; Solvent; Reagent/catalyst;	94%
With potassium carbonate In N,N-dimethyl-formamide at 50℃; for 24h;	94%

3β-hydroxyoleanane-12-en-28-oicacid(4-bromobutyl) ester + (R)-1,2-dithiolane-3-pentanoic acid (1200-22-2) → [((5-((R)-1,2-dithiolan-3-yl)pentanoyl)oxy)butyl]-3β-hydroxyolean-12-en-28-oate

Conditions	Yield
With potassium carbonate In N,N-dimethyl-formamide at 50℃; for 24h;	94%

2,2,2-tris(hydroxymethyl)ethylamine (7332-39-0) + (R)-1,2-dithiolane-3-pentanoic acid (1200-22-2) → trometamol (R)-α-lipoate

Conditions	Yield
In ethanol at 0 - 60℃; Product distribution / selectivity;	93.1%

choline chloride (67-48-1) + (R)-1,2-dithiolane-3-pentanoic acid (1200-22-2) → R-lipoic acid choline ester chloride

Conditions	Yield
With dmap; dicyclohexyl-carbodiimide In toluene at 35℃; for 18h; Cooling with ice; Green chemistry;	93%
With dmap; dicyclohexyl-carbodiimide In chloroform at 35℃; for 18h; Solvent; Reagent/catalyst; Temperature;	89%

(E)-15,19-dimethyl-3,6,9,12-tetraoxaicosa-14,18-dien-1-ol + (R)-1,2-dithiolane-3-pentanoic acid (1200-22-2) → C26H46O6S2

Conditions	Yield
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 30℃; for 10h;	92.1%

(R)-1,2-dithiolane-3-pentanoic acid (1200-22-2) + 2-chloro-ethanol (107-07-3) → (R)-lipoic acid 2-chloroethyl ester

Conditions	Yield
With dmap; dicyclohexyl-carbodiimide In dichloromethane at 35℃; for 18h; Cooling with ice;	92%

L-Lysine hydrochloride (657-27-2, 10098-89-2) + (R)-1,2-dithiolane-3-pentanoic acid (1200-22-2) → R(+)-lipoic acid L-lysine salt

Conditions	Yield
Stage #1: (R)-1,2-dithiolane-3-pentanoic acid With sodium ethanolate In ethanol at 20℃; Stage #2: L-Lysine hydrochloride In acetone at 55 - 60℃; for 2h; Concentration; Temperature;	92%

Upstream product

• 97961-65-4 (+)-isopropyl lipoate 
• 1225192-30-2 (R)-5-[1,2]dithiolan-3-yl-pentanoic acid methylamide 
• 1225192-32-4 (R)-5-[1,2]dithiolan-3-yl-pentanoic acid propylamide 
• 1225192-34-6 (R)-5-[1,2]dithiolan-3-yl-pentanoic acid isopropylamide 
• 1225192-38-0 (R)-5-[1,2]dithiolan-3-yl-pentanoic acid phenethylamide 
• 1225192-41-5 (R)-5-[1,2]dithiolan-3-yl-pentanoic acid (3-phenyl-propyl)amide 
• 1225192-43-7 (R)-5-[1,2]dithiolan-3-yl-pentanoic acid (4-phenyl-butyl)amide 
• 1225192-45-9 (R)-5-[1,2]dithiolan-3-yl-pentanoic acid cyclopentylamide 
• 1225192-55-1 (R)-5-[1,2]dithiolan-3-yl-pentanoic acid n-pentylamide 
• 1225192-61-9 (R)-N-benzyl-5-(1,2-dithiolan-3-yl)pentanamide 
• 1225192-62-0 (R)-5-[1,2]dithiolan-3-yl-pentanoic acid N-(3-hydroxy-4-methoxybenzyl)amide 
• 1225192-63-1 (R)-5-[1,2]dithiolan-3-yl-pentanoic acid N-(cyclopropylmethyl)amide 
• 1225192-64-2 (R)-5-[1,2]dithiolan-3-yl-pentanoic acid N-(buten-4-yl)amide 
• 1225192-66-4 (R)-5-[1,2]dithiolan-3-yl-pentanoic acid N-(3-acetoxy-4-methoxybenzyl)amide 

Downstream Products

• 1365619-36-8 2-(2-(4-N-(4-(1,2-dithiolane)pentanecarboxy)aminophenyl))ethylamino-N⁽⁶⁾-(2,2-diphenylethyl)adenosine-5'-N-ethylcarboxamide 
• 1365619-29-9 2-(2-(4-N-(4-(1,2-dithiolane)pentanecarboxy)aminophenyl))ethylamino-2',3'-isopropylideneadenosine-5'-N-ethylcarboxamide 
• 119365-69-4 (R)-6,8-dimercaptooctanoic acid 
• 108015-78-7 5-(R)-1ξ-oxo-1λ⁴-[1,2]dithiolan-3-yl-valeric acid 

Relevant articles and documents

Enantioselective Synthesis of R-(+)-α-Lipoic Acid

The title compound has been synthesised in an enantioselective manner from achiral precursors using the Sharpless asymmetric epoxidation as the key step in the reaction sequence.

Coevolution of the Activity and Thermostability of an ?-Keto Ester Reductase for Better Synthesis of an (R)-α-Lipoic Acid Precursor

In this work, we have identified a significantly improved variant (S131Y/Q252I) of the natural ?-keto ester reductase CpAR2 from Candida parapsilosis for efficiently manufacturing (R)-8-chloro-6-hydroxyoctanoic acid [(R)-ECHO] through co-evolution of activity and thermostability. The activity of the variant CpAR2S131Y/Q252I towards the ?-keto ester ethyl 8-chloro-6-oxooctanoate was improved to 214 U mg?1—from 120 U mg?1 in the case of the wild-type enzyme (CpAR2WT)—and the half-deactivating temperature (T50, for 15 min incubation) was simultaneously increased by 2.3 °C in relation to that of CpAR2WT. Consequently, only 2 g L?1 of lyophilized E. coli cells harboring CpAR2S131Y/Q252I and a glucose dehydrogenase (GDH) were required in order to achieve productivity similar to that obtained in our previous work, under optimized reaction conditions (530 g L?1 d?1). This result demonstrated a more economical and efficient process for the production of the key (R)-α-lipoic acid intermediate ethyl 8-chloro-6-oxooctanoate.

Microwave-assisted resolution of α-lipoic acid catalyzed by an ionic liquid co-lyophilized lipase

The combination of the ionic liquid co-lyophilized lipase and microwave irradiation was used to improve enzyme performance in enantioselective esterification of α-lipoic acid. Effects of various reaction conditions on enzyme activity and enantioselectivity were investigated. Under optimal condition, the highest enantioselectivity (E = 41.2) was observed with a high enzyme activity (178.1 μmol/h/mg) when using the ionic liquid co-lyophilized lipase with microwave assistance. Furthermore, the ionic liquid co-lyophilized lipase exhibited excellent reusability under low power microwave.

Synthesis method R -lipoic acid

A synthesis method of R -lipoic acid comprises N - (5 -bromopentyl) phthalimide and zinc powder. Lithium chloride, trimethylchlorosilane, 1,2 - dibromoethane and tetrahydrofuran are mixed, reacted to form a zinc bromide intermediate, and 3 - {[2 - (trimethylsilyl) ethoxy] methoxy} propionyl chloride is then reacted with a zinc bromide intermediate. The obtained intermediate -1 is subjected to a hydrazine decomposition reaction. The obtained intermediate -2 is subjected to a catalytic oxidation reaction. The obtained intermediate -3 is subjected to an esterification reaction. The nearly smooth Candida tropicalis is introduced into a fermentation medium for amplification culture, and the obtained resting cells are suspended in a buffer aqueous solution and the obtained intermediate -4 is added for enzyme-catalyzed chiral reduction reaction. The resulting intermediate -5 is subjected to deprotection reaction. The resulting intermediate -6 is subjected to a chlorination reaction. The resulting intermediate -7 was subjected to a cyclization reaction. The obtained intermediate -8 was subjected to a hydrolysis reaction to obtain a finished product.

Preparation method of D-lipoic acid

The invention relates to a preparation method of d-lipoic acid. The preparation method comprises the following steps: carrying out free reaction on a compound shown as a formula I under the action ofcitric acid, washing with water, concentrating, and eluting to obtain the d-lipoic acid. According to the scheme for preparing the d-lipoic acid, the generation of polymer related substances in the preparation process of the d-lipoic acid can be remarkably reduced.