Preparation method of dibenzo[b,f][1,4]thiazepine-11-[10H]one_Kain Industrial Additive

Background and overview^[1]

Dibenzo[b,f][1,4]thiazepin-11-[10H]one is a key intermediate in the preparation of quetiapine. Quetiapine, generally sold as the hemifumarate salt. It is an antipsychotic drug developed by AstraZeneca UKlimited (AstraZeneca Pharmaceutical Company). It was first launched in the UK in November 1997 and is used to treat schizophrenia. It has strong antipsychotic effects and causes fewer symptoms. Extrapyramidal syndrome.

Preparation^[1]

Preparation of 2-carboxydiphenyl sulfide (compound II)

Add 150mL tetralin, o-chlorobenzoic acid (15.6g, 0.1mol), and copper powder (0.32g, 0.005mol) into the reaction bottle. When the system drops to about 0°C, add hydrogen in sequence while stirring. Sodium oxide (6.0g, 0.15mol), thiophenol (11.1g, 0.1mol), after addition, raise the temperature to 130°C and react for 6 hours (TLC monitoring during the reaction). After the reaction is completed, cool, add 100mL of water, and filter to remove copper. powder, the filtrate was separated into layers, and the pH of the aqueous phase was adjusted to 2-3 with hydrochloric acid to precipitate a large amount of white solid. 20.5g of crude product was obtained by suction filtration, with a yield of 89% and a purity (HPLC) of 97.8%. Molecular formula: CHOS; molecular weight: 230.0; MS (m/z): 231.0 (M+H).

Preparation of thioxanthone (III)

Add 2-carboxydiphenyl sulfide (23g, 0.1mol, compound II) into the reaction bottle, add 100mL toluene to dissolve, when the ice bath cools to about 0°C, add 20mL concentrated sulfuric acid dropwise, and raise the temperature after the addition is completed Continue stirring the reaction for 1 hour at 80°C, and monitor the progress of the reaction with TLC. After the reaction is completed, pour the reactants into water, separate the liquids, wash the organic phase with water until neutral, dry, remove toluene, and recrystallize with ethanol to obtain a light yellow crude product. 16g, yield: 75.5%. Purity (GC): 98.2%. Molecular formula: CHOS; molecular weight: 212.0; MS (m/z): 213.0 (M). H NMR (400MHz, CDCl) δ8.52 (d, J = 8.0 Hz, 2H), 7.52-7.43 (m, 4H), 7.37 (t, J = 7.6 Hz, 2H); C NMR (100 MHz, CDCl) δ 179 .2, 137.1, 132.1, 129.6, 129.0, 126.1, 125.7; melting point: 207.5℃-209.1℃.

Preparation of thioxanthone oxime (compound VI)

Add thioxanthone (21.2g, 0.1mol, compound III) into the reaction flask, add 100mL ethanol to dissolve, then add hydroxylamine hydrochloride (7.65g, 0.11mol, CAS: 5470-11-1), and add After the reaction is completed, the temperature is raised to reflux and the reaction is stirred for 3 hours. The progress of the reaction is monitored by TLC. After the reaction is completed, most of the solvent is spun off, the crystals are precipitated by cooling, and 21.1 g of white solid is obtained by suction filtration. Yield: 93%. Purity (HPLC): 99.1%. Molecular formula: CHNOS; molecular weight: 227.0; MS (m/z): 228.0 (M).

Preparation of dibenzo[b,f][1,4]thiazepin-11-(10H)one (compound V)

Add thioxanthone oxime (22.7g, 0.1mol, compound IV) into the reaction bottle, add 100mL anhydrous toluene to dissolve, then add p-toluenesulfonic acid (0.95g, 0.005mol, CAS: 104 -15-4), after the addition is completed, raise the temperature to reflux and stir the reaction overnight. TLC monitors the progress of the reaction. After the reaction is completed, spin off most of the solvent, cool to precipitate the crystals, and obtain 18.5g of white solid by suction filtration. Yield: 81.5% . Purity (HPLC): 97.0%. Molecular formula: CHNOS; molecular weight: 227.0; MS (m/z): 228.0 (M).

Apply^[1]

For the preparation of quetiapine, the route is as follows:

Under the action of chlorinating reagent, 10,11-dihydrodiphenyl[b,f][1,4]oxazepine-11-one is subjected to chlorination reaction to obtain 11-chloro-dibenzo [b,f][1,4]thiazepine. In the presence of a base, the obtained 11-chloro-dibenzo[b,f][1,4]thiazepine reacts with 2-(2-hydroxyethoxy)ethylpiperazine to obtain quetiapine ; The obtained quetiapine is salted with fumaric acid in an alcohol solvent to obtain the quetiapine semifumarate.

Main reference materials

[1] [China invention, China invention authorization] CN201610282040.9 A synthesis method of quetiapine