A method for preparing an oxygen-containing carotenoid

Abstract

The application provides a preparation method of an oxygen-containing carotenoid, in particular a preparation method of canthaxanthin (I-a) or astaxanthin (I-b), and the preparation method comprises the following steps: (1) C15-alcohol (II) is reacted with 2-mercaptobenzothiazole (MBT) to prepare C15-benzothiazole sulfide (III), and the C15-benzothiazole sulfide (III) is further oxidized to prepare C15-benzothiazole sulfone (IV); (2) the C15-benzothiazole sulfone (IV) is coupled with C10-dialdehyde (V) to prepare the target product: canthaxanthin (I-a) or astaxanthin (I-b); the method has low raw material cost, avoids the use of phosphorus salt in the traditional synthesis route, and the by-product 2-hydroxybenzothiazole is an important intermediate for synthesizing the herbicide thiobencarb, and also has economic benefits; and the method provides an efficient, economical and environmentally-friendly solution for large-scale clean production of canthaxanthin and astaxanthin.

Description

Technical Field

[0001] This invention belongs to the field of fine organic synthesis and relates to a method for preparing oxygen-containing carotenoids, specifically a method for preparing canthaxanthin (I-a) or astaxanthin (I-b). Background Technology

[0002] Canthaxanthin, also known as canthaxanthin, is an oxygen-containing carotenoid that is naturally found in mushrooms, crustaceans, fish, and algae. It has significant antioxidant properties and good coloring ability, and is widely used in the feed industry for coloring poultry. Its products can increase the color of poultry and bird egg yolks, thereby enhancing the market value of poultry products.

[0003] Astaxanthin is also an oxygen-containing carotenoid. Like other carotenoids, astaxanthin is a fat-soluble pigment and is widely used in meat and poultry coloring. At the same time, astaxanthin also exhibits good antioxidant properties, helping to improve the health of poultry, delay the aging process, and improve production efficiency.

[0004] Canthaxanthin and astaxanthin have very similar molecular structures, both containing the same conjugated double bond system. Theoretically, their chemical synthesis pathways can be formed by combining different synthetic fragments, which can be gradually constructed into the final molecular structure through different chemical reactions.

[0005] Various technical routes for the preparation of canthaxanthin by oxidizing β-carotene have been reported in US4212827, CN1277191, CN101633633, CN1793098 and CN108250118. All of these routes suffer from problems such as low reaction yield, poor catalyst stability, difficulty in recycling and reuse, generation of halogen-containing wastewater, and environmental unfriendliness.

[0006] CN115772108 reported a route for synthesizing a key intermediate of canthaxanthin from C15+C10→C25, in which C15-phosphine salt reacts with C10-dialdehyde to obtain C25-aldehyde intermediate.

[0007] CN111410623 reported a synthetic route for canthaxanthin via the C15+C10+C15→C40 reaction, which involves the condensation reaction of two molecules of C15-phosphate salt with C10-dialdehyde to prepare canthaxanthin.

[0008] CN101454280 reported a synthetic route for astaxanthin via C15+C10+C15→C40, which involves the condensation reaction of two molecules of C15-phosphate salt with C10-dialdehyde to prepare astaxanthin.

[0009] In the above synthetic routes, the construction of carbon chains for canthaxanthin and astaxanthin mainly relies on the Wittig reaction to complete the splicing of various fragments. This requires a large amount of phosphine salts, and the by-product phosphorus compounds cause significant water pollution and are difficult to process and recycle, which obviously brings environmental problems to large-scale production.

[0010] According to the literature Arch. Biochem. Biophys. 2015, 572, 142-150 and Adv. Synth. Catal. 2024, 366, 82-90, the authors constructed carbon-carbon double bonds through the reaction of benzothiazole sulfone with aldehydes and successfully prepared lycopene and β-carotene using this method, which is a novel green chemistry method. However, it suffers from the problems of expensive palladium catalysts and low overall yield. Currently, there are no literature reports on the application of this method to the synthesis of canthaxanthin or astaxanthin.

[0011] Therefore, developing a synthesis process for canthaxanthin and astaxanthin that is high-yield, low-cost, environmentally friendly, and produces less waste is a technical problem that urgently needs to be solved in this field. Summary of the Invention

[0012] In view of the shortcomings of the existing technology, the purpose of this invention is to provide a method for preparing oxygen-containing carotenoids, specifically a method for preparing canthaxanthin (I-a) or astaxanthin (I-b). This method has many advantages such as high yield, mild reaction conditions, low cost of raw materials and catalysts, low waste generation, and environmental friendliness.

[0013] The preparation method of the oxygen-containing carotenoids of the present invention specifically refers to the preparation method of canthaxanthin (I-a, X=H) or astaxanthin (I-b, X=OH), comprising the following steps:

[0014] (1) Preparation of C15-BT(Ⅲ): Under the protection of an inert gas, C15-alcohol(Ⅱ), 2-mercaptobenzothiazole (MBT), solvent, acid and catalyst were added in sequence, and the mixture was stirred thoroughly and the reaction temperature was maintained until the reaction was complete, thus obtaining C15-BT(Ⅲ).

[0015] (2) Preparation of C15-BTS(Ⅳ): Under the protection of inert gas, C15-BT(Ⅲ) and solvent are thoroughly mixed and uniform, catalyst A is added to prepare solution 1; oxidant is taken separately, catalyst B is added and stirred evenly, and then added dropwise to solution 1. After the addition is completed, the temperature is maintained until the reaction is complete, and C15-BTS(Ⅳ) is obtained.

[0016] (3) Preparation of product (Ⅰ): Under the protection of inert gas, C15-BTS (Ⅳ) and C10-dialdehyde (Ⅴ) are thoroughly mixed with solvent. The base is slowly added at the reaction temperature. After the addition is complete, the temperature is maintained until the reaction is complete to obtain product (Ⅰ).

[0017] The reaction formula is as follows:

[0018]

[0019] The core of this preparation method lies in replacing the use of phosphate salts in the traditional method with benzothiazole sulfone (BTS): first, benzothiazole sulfide (III) is prepared by reacting C15-ol (II) with 2-mercaptobenzothiazole (MBT), and then benzothiazole sulfone, namely C15-BTS (IV), is prepared by oxidation reaction. Then, the target product is prepared by reacting with C10-dialdehyde (V) under the action of alkali: canthaxanthin (I-a) or astaxanthin (I-b).

[0020] In this invention, the C15-alcohol (II) in step (1) is the corresponding C15-tertiary alcohol, C15-primary alcohol, or a mixture of the two;

[0021] The molar ratio of 2-mercaptobenzothiazole (MBT) to C15-ol (II) in step (1) is 1.0 to 3.0:1, preferably 1.2 to 1.4:1, and more preferably 1.33:1;

[0022] The solvent in step (1) is one or more of methanol, ethanol, isopropanol, n-butanol, tert-butanol, toluene, xylene, cyclopentyl methyl ether, ethyl acetate, dichloromethane, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran or N,N-dimethylformamide, preferably dichloromethane;

[0023] The acid in step (1) is one or more of formic acid, acetic acid, hydrochloric acid, phosphoric acid or sulfuric acid, preferably acetic acid;

[0024] The molar ratio of the acid used in step (1) to C15-alcohol (II) is 0.01 to 2.0:1, preferably 0.01 to 0.20:1, and more preferably 0.05:1;

[0025] The catalyst in step (1) is a quaternary ammonium salt compound, including one or more of trioctylmethylammonium sulfate, tetrabutylammonium chloride, tetrabutylammonium bromide or tetrabutylammonium iodide, preferably trioctylmethylammonium sulfate;

[0026] The molar ratio of the catalyst used in step (1) to C15-ol (II) is 0.01 to 0.5:1, preferably 0.01 to 0.10:1, and more preferably 0.02:1;

[0027] The reaction temperature in step (1) is 0 to 100°C, preferably 30 to 50°C, and more preferably 40°C.

[0028] In this invention, the solvent in step (2) is one or more of methanol, ethanol, ethylene glycol, isopropanol, n-butanol, tert-butanol, toluene, xylene, cyclopentyl methyl ether, ethyl acetate, dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran or N,N-dimethylformamide, preferably dichloromethane;

[0029] After the reaction in step (1) is completed, the mixture is allowed to stand and separate into layers. The organic phase is washed with water and the solvent is recovered under reduced pressure. The crude C15-BT(Ⅲ) product is then directly introduced into the reaction in step (2).

[0030] The catalyst A in step (2) is a quaternary ammonium salt compound, including one or more of trioctylmethylammonium sulfate, tetrabutylammonium chloride, tetrabutylammonium bromide or tetrabutylammonium iodide, preferably trioctylmethylammonium sulfate;

[0031] In step (2), the molar ratio of catalyst A to C15-BT(Ⅲ) is 0.01 to 0.5:1, preferably 0.01 to 0.10:1, and more preferably 0.01:1;

[0032] The oxidant in step (2) is one or more of hydrogen peroxide, urea peroxide, peroxyformic acid, peracetic acid, tert-butyl hydroperoxide or m-chloroperoxybenzoic acid, preferably hydrogen peroxide;

[0033] The molar ratio of the oxidant used in step (2) to C15-BT(Ⅲ) is 2.0 to 6.0:1, preferably 2.0 to 3.0:1, and more preferably 2.5:1;

[0034] The catalyst B in step (2) is one or more of sodium acetate, sodium tungstate, ammonium heptamolybdate or 2,2,6,6-tetramethylpiperidine oxide, preferably sodium tungstate;

[0035] In step (2), the molar ratio of catalyst B to C15-BT(Ⅲ) is 0.01 to 0.5:1, preferably 0.01 to 0.10:1, and more preferably 0.03:1;

[0036] The reaction temperature in step (2) is -10 to 80°C, preferably -5 to 10°C, and more preferably 0°C.

[0037] After the reaction in step (2) is completed, sodium bisulfite solution is added to quench the reaction, and then the phases are separated. The aqueous phase is extracted with dichloromethane, and the resulting organic phase is washed, dried and concentrated to obtain crude C15-BTS (Ⅳ) which is then introduced into step (3).

[0038] In this invention, the molar ratio of C15-BTS(Ⅳ) to C10-dialdehyde(Ⅴ) in step (3) is 2.0 to 5.0:1, preferably 2.0 to 3.0:1, and more preferably 2.3:1;

[0039] The solvent in step (3) is one or more of methanol, ethanol, isopropanol, n-butanol, tert-butanol, toluene, xylene, cyclopentyl methyl ether, ethyl acetate, dichloromethane, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran or N,N-dimethylformamide, preferably dichloromethane;

[0040] The alkali mentioned in step (3) is one or more of sodium hydroxide, potassium hydroxide, sodium methoxide, potassium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), sodium bis(trimethylsilyl)amino, lithium bis(trimethylsilyl)amino, lithium diisopropylamino, or n-butyllithium, preferably sodium methoxide;

[0041] The molar ratio of the amount of alkali to C10-dialdehyde (V) in step (3) is 0.5 to 5.0:1, preferably 2.0 to 3.0:1, and more preferably 2.5:1;

[0042] The reaction temperature in step (3) is -78 to 80°C, preferably 30 to 50°C, and more preferably 40°C.

[0043] Compared with the prior art, the beneficial effects of the present invention are reflected in:

[0044] (1) 2-Mercaptobenzothiazole (MBT) is cheap and readily available, with low raw material costs;

[0045] (2) No expensive palladium catalyst is required;

[0046] (3) The reaction does not involve phosphorus-containing compounds, making it environmentally friendly;

[0047] (4) It generates less waste, and the main byproduct 2-hydroxybenzothiazole is an important intermediate in the synthesis of the herbicide haloxyfop-R-methyl, which also has economic benefits.

[0048] (5) The reaction conditions are mild and the process is simple, making it suitable for large-scale production. Detailed Implementation

[0049] Example 1

[0050] Preparation of C15-BT(Ⅲ, X=H)

[0051] Under nitrogen protection, 30.10 g (0.10 mol) of C15-ol (II), 100 ml of dichloromethane, 22.70 g (0.133 mol) of 2-mercaptobenzothiazole (MBT), 0.95 g (0.002 mol) of trioctylmethylammonium sulfate, and 0.31 g (0.005 mol) of acetic acid were added sequentially to a stirred 250 ml three-necked round-bottom flask. The reaction was carried out at 40 °C, and the reaction progress was monitored by liquid chromatography. After the reaction was completed, the mixture was transferred to a separatory apparatus and allowed to stand for separation. The organic phase was washed once with 100 ml of water, and the dichloromethane was recovered under reduced pressure to obtain 56.27 g of crude C15-BT (III, X=H) (purity 61%, yield 90%).

[0052] The data obtained after sampling and purification are as follows:

[0053] UV (MeOH): λmax = 227nm, 294nm, 302nm.

[0054] IR (KBr): 3061, 2960, 2924, 2866, 1662, 1587, 1456, 1427, 1352, 1332,1309, 993, 756, 727.

[0055] 1 H NMR (400 MHz, CDCl3) δ 7.86 (dd, J = 18.2, 8.1 Hz, 1H), 7.75 (dd, J= 8.1, 8.1 Hz, 1H), 7.42 (td, J = 7.9, 1.4 Hz, 1H), 7.30 (td, 1H), 6.22 (s,2H), 5.81 (td, J = 8.0, 1.3 Hz, 1H), 4.19 (d, J = 8.0 Hz, 2H), 2.49 (t, J =6.9 Hz, 2H), 1.97 (s, 3H), 1.87-1.83 (m, 2H), 1.81 (s, 3H), 1.16 (s, 6H).

[0056] HPLC / MS (APCI+): 384 (M + 1), C 22 H 25 ONS2 calculated for 383.13776.

[0057] MS (EI): 383 (M) +, 100%), 368, 350, 336, 327, 285, 249, 232, 217, 167,147, 119, 69, 55.

[0058] Example 2

[0059] Preparation of C15-BTS (Ⅳ, X=H)

[0060] Under nitrogen protection, 31.13 g (0.050 mol) of C15-BT(Ⅲ, X=H), 50 ml of dichloromethane, and 0.23 g (0.0005 mol) of trioctylmethylammonium sulfate were added sequentially to a stirred 250 ml three-necked round-bottom flask; 15.46 g of... 0.125 mol of hydrogen peroxide was added to 0.44 g (0.0015 mol) of sodium tungstate and stirred until homogeneous. The mixture was then slowly added dropwise to the reaction solution at 0 °C, with the reaction temperature controlled to not exceed 5 °C throughout the process. After the addition was complete, the reaction temperature was maintained and the reaction continued. The liquid phase was used to monitor the reaction progress. After the reaction was completed, 100 g of a 5 wt% sodium bisulfite solution was added and stirred for 0.5 h. The mixture was then transferred to a separatory apparatus and allowed to stand for separation. The aqueous phase was extracted twice with 50 ml of dichloromethane and combined with the aqueous phase. The aqueous phase was then washed once with 100 ml of saturated brine. The organic phase was separated, dried with sodium sulfate, filtered, and the dichloromethane was concentrated under reduced pressure to obtain 34.26 g of crude C15-BTS (Ⅳ, X=H) (purity 52%, yield 86%).

[0061] The data obtained after sampling and purification are as follows:

[0062] UV (MeOH): λmax = 223nm, 281nm.

[0063] IR (KBr):2960, 2926, 2866, 1662, 1471, 1332, 1149, 763, 729.

[0064] 1 H NMR (600 MHz, CDCl3) δ 8.23 ​​(d, J = 7.3 Hz, 1H), 8.01 (d, J = 7.3Hz, 1H), 7.68-7.57 (m, 2H), 6.18 (d, J = 2.0 Hz, 2H), 5.58 (td, J = 8.1, 1.4Hz, 1H), 4.42 (d, J = 8.1 Hz, 2H), 2.48 (t, J = 6.8 Hz, 2H), 1.85 -1.78 (m,5H), 1.74 (s, 3H), 1.10 (s, 6H).

[0065] HPLC / MS (APCI+): 416 (M + 1), C 22 H 25 O3NS2 calculated for 415.12759.

[0066] MS (EI): 415 (M + ), 352, 336, 217, 199, 189, 161, 147, 119, 91, 69,55.

[0067] Example 3

[0068] Preparation of canthaxanthin (I-a)

[0069] Under nitrogen protection, 200 ml of dichloromethane, 8.54 g (0.050 mol) of C10-dialdehyde (V), and 63.50 g (0.115 mol) of C15-BTS (Ⅳ, X=H) were added sequentially to a stirred 500 ml three-necked round-bottom flask. 45.00 g (0.125 mol) of sodium methoxide-methanol solution was slowly added dropwise at 40 °C. After the addition was complete, the reaction temperature was maintained and the reaction continued. The liquid phase was monitored to track the reaction progress. After the reaction was completed, 200 ml of saturated ammonium chloride aqueous solution was added. The mixture was transferred to a separatory apparatus and allowed to stand for separation. The organic phase was separated and washed once with 200 ml of saturated brine. The organic phase was then dried with dry sodium sulfate. After filtration, the dichloromethane was recovered under reduced pressure to obtain 71.65 g of crude canthaxanthin (Ⅰ-a) (purity 33%, yield of C10-dialdehyde (V) 84%).

[0070] The data obtained after sampling and purification are as follows:

[0071] UV (MeOH): λmax = 474nm.

[0072] IR (KBr): 3028, 2958, 2922, 2860, 1660, 1558, 1446, 1350, 1199, 1093,966, 910, 732.

[0073] 1 H NMR (400 MHz, CDCl3) δ 6.71 - 6.59 (m, 4H), 6.46 - 6.19 (m, 10H), 2.56 - 2.45 (m, 4H), 1.99 (d, J = 6.5 Hz, 12H), 1.85 (d, J = 15.6 Hz, 10H),1.19 (s, 12H).

[0074] HPLC / MS (APCI+): 565 (M + 1), C 40 H 52 O2 was calculated for 564.39673.

[0075] MS (EI): 564 (M + , 100%), 508, 472, 413, 361, 347, 255, 203, 209, 145,133, 105, 69, 55.

[0076] Example 4

[0077] Preparation of C15-BT(Ⅲ, X=H)

[0078] Under nitrogen protection, 30.10 g (0.10 mol) of C15-ol (II), 100 ml of ethyl acetate, 22.72 g (0.133 mol) of 2-mercaptobenzothiazole (MBT), 0.95 g (0.002 mol) of trioctylmethylammonium sulfate and 0.61 g (0.01 mol) of acetic acid were added sequentially to a stirred 250 ml three-necked round-bottom flask. The reaction was carried out at 50 °C, and the reaction was monitored by liquid chromatography. After the reaction was completed, 20 ml of water was added, and the mixture was transferred to a separatory apparatus to stand and separate into layers. The organic phase was washed once with 100 ml of water, and the ethyl acetate was concentrated under reduced pressure to obtain 54.43 g of crude C15-BT (III, X=H) (purity 57%, yield 81%).

[0079] Example 5

[0080] Preparation of C15-BT(Ⅲ, X=H)

[0081] Under nitrogen protection, 15.05 g (0.050 mol) of C15-ol (II), 50 mL of dichloromethane, 11.45 g (0.067 mol) of 2-mercaptobenzothiazole (MBT), and 3.03 g (0.05 mol) of acetic acid were added sequentially to a stirred 100 mL three-necked round-bottom flask. The reaction was carried out at 40 °C, and the reaction progress was monitored using a liquid phase. No product was detected after 48 hours of reaction. The results indicate that this step of the reaction cannot occur without the addition of catalysts such as trioctylmethylammonium sulfate.

[0082] Example 6

[0083] Preparation of C15-BTS (Ⅳ, X=H)

[0084] Under nitrogen protection, 6.22 g (0.010 mol) of C15-BT(Ⅲ, X=H) and 15 ml of ethanol were added sequentially to a stirred 100 ml three-necked round-bottom flask. Separately, 3.11 g (0.025 mol) of hydrogen peroxide and 0.10 g (0.0003 mol) of sodium tungstate were added and stirred until homogeneous. The mixture was then slowly added dropwise to the reaction solution at 0 °C, with the reaction temperature controlled to not exceed 5 °C throughout the process. After the addition was complete, the reaction temperature was maintained and the reaction was continued. The liquid phase was monitored to track the reaction progress. After the reaction was completed, 20 g of a prepared 5 wt% sodium bisulfite solution and 30 ml of ethyl acetate were added. After stirring for 0.5 h, the mixture was transferred to a separatory apparatus and allowed to stand for separation. The aqueous phase was extracted once with 30 ml of ethyl acetate and combined with the organic phase. The solvent was concentrated under reduced pressure to obtain 8.16 g of crude C15-BTS(Ⅳ, X=H) (purity 41%, yield 81%).

[0085] Example 7

[0086] Preparation of C15-BTS (Ⅳ, X=H)

[0087] Under nitrogen protection, 6.22 g (0.010 mol) of C15-BT(Ⅲ, X=H) and 15 ml of dichloromethane were added sequentially to a stirred 100 ml three-necked round-bottom flask. Separately, 3.09 g (0.025 mol) of hydrogen peroxide was added to 0.10 g (0.0003 mol) of sodium tungstate, and after thorough mixing, the solution was slowly added dropwise to the reaction mixture at 0 °C. The reaction temperature was controlled to not exceed 5 °C throughout the process. After the addition was complete, the reaction temperature was maintained and the reaction was continued. The reaction progress was monitored using a liquid phase. After 18 hours of reaction, no product was formed. The results indicate that without the addition of catalysts such as trioctylmethylammonium sulfate, this step of the reaction either does not occur or proceeds extremely slowly.

[0088] Example 8

[0089] Preparation of canthaxanthin (I-a)

[0090] Under nitrogen protection, 100 ml of dichloromethane, 3.42 g (0.020 mol) of C10-dialdehyde (V), and 34.26 g (0.043 mol) of C15-BTS (Ⅳ, X=H) were added sequentially to a stirred 250 ml three-necked round-bottom flask. 7.77 g (0.050 mol) of DBU was slowly added dropwise at 25 °C. After the addition was complete, the temperature was raised to 45 °C to continue the reaction. The reaction was monitored by liquid chromatography. After the reaction was completed, 100 ml of saturated ammonium chloride aqueous solution was added. The mixture was transferred to a separatory apparatus and allowed to stand for separation. The organic phase was separated and washed once with 100 ml of saturated brine. The organic phase was then dried with dry sodium sulfate. After filtration, the dichloromethane was recovered under reduced pressure to obtain 38.08 g of crude canthaxanthin (Ⅰ-a) (purity 20%, yield of C10-dialdehyde (V) 70%).

[0091] Example 9

[0092] Preparation of C15-BT(Ⅲ, X=OH)

[0093] Under nitrogen protection, 38.60 g (0.10 mol) of C15-ol (II), 100 ml of dichloromethane, 22.70 g (0.133 mol) of 2-mercaptobenzothiazole (MBT), 0.95 g (0.0020 mol) of trioctylmethylammonium sulfate, and 0.61 g (0.010 mol) of acetic acid were added sequentially to a stirred 250 ml three-necked round-bottom flask. The reaction was carried out at 40 °C for 4 hours, and the reaction was monitored by liquid chromatography. After the reaction was completed, 20 ml of water was added, and the mixture was transferred to a separatory apparatus to stand and separate into layers. The organic phase was washed once with 100 ml of water, and the dichloromethane was recovered under reduced pressure to obtain 62.32 g of crude C15-BT(III, X=OH) (purity 58%, yield 91%).

[0094] The data obtained after sampling and purification are as follows:

[0095] UV (MeOH): λmax = 226nm, 293nm, 302nm.

[0096] IR (KBr): 3483, 2962, 2926, 2864, 1735, 1666, 1456, 1427, 1309, 1130,1074, 991, 756, 727.

[0097] 1 H NMR (400 MHz, CDCl3) δ 7.89 (d, J = 8.2 Hz, 1H), 7.76 (d, J = 7.9Hz, 1H), 7.43 (t, J = 7.0 Hz, 1H), 7.31 (t, J = 7.0 Hz, 1H), 6.27 (d, J =16.1 Hz, 1H), 6.19 (d, J = 16.3 Hz, 1H), 5.84 (t, J = 7.6 Hz, 1H), 4.31 (dd,J = 13.9, 5.6 Hz, 1H), 4.19 (d, J = 8.1 Hz, 2H), 2.15 (dd, J = 12.7, 5.6 Hz,1H), 1.97 (s, 3H), 1.88 (s, 3H), 1.29 (s, 3H), 1.26 (d, J = 11.1 Hz, 2H), 1.17 (s, 3H).

[0098] HPLC / MS (APCI+): 400 (M + 1), C 22 H 25 O2NS2 calculated for 399.13267.

[0099] MS (EI): 399(M + , 100%), 384, 366, 352, 327, 284, 265, 233, 215, 187,167, 119, 91, 55.

[0100] Example 10

[0101] Preparation of C15-BTS(Ⅳ, X=OH)

[0102] Under nitrogen protection, 35.20 g (0.05 mol) of C15-BT(Ⅲ, X=OH), 50 ml of dichloromethane, and 0.23 g (0.0005 mol) of trioctylmethylammonium sulfate were added sequentially to a stirred 250 ml three-necked round-bottom flask; 15.45 ml of... 0.125 mol of hydrogen peroxide was added to 0.44 g (0.0015 mol) of sodium tungstate and stirred until homogeneous. The mixture was then slowly added dropwise to the reaction solution at 0 °C, with the reaction temperature controlled to not exceed 5 °C throughout the process. After the addition was complete, the reaction temperature was maintained and the reaction continued. The liquid phase was used to monitor the reaction progress. After the reaction was completed, 50 g of a prepared 10 wt% sodium bisulfite solution was added and stirred for 0.5 h. The mixture was then transferred to a separatory apparatus and allowed to stand for separation. The aqueous phase was extracted twice with 50 ml of dichloromethane and combined with the aqueous phase. The aqueous phase was then washed once with 100 ml of saturated brine. The organic phase was separated, dried with dry sodium sulfate, filtered, and the dichloromethane was recovered under reduced pressure to obtain 37.54 g of crude C15-BTS(Ⅳ, X=OH) (purity 48%, yield 84%).

[0103] The data obtained after sampling and purification are as follows:

[0104] UV (MeOH): λmax = 218nm, 280nm.

[0105] IR (KBr):3483, 2964, 2926, 2868, 1666, 1469, 1330, 1278, 1151, 1074,912, 763, 731, 634.

[0106] 1H NMR (400 MHz, CDCl3) δ 8.23 ​​(dd, J = 7.6, 1.4 Hz, 1H), 8.00 (d, J =2.8 Hz, 1H), 7.66 - 7.58 (m, 2H), 6.25 - 6.11 (m, 2H), 5.61 (t, J = 7.9 Hz,1H), 4.42 (d, J = 8.3 Hz, 2H), 4.30 (dd, J = 13.9, 5.6 Hz, 1H), 2.13 (dd, J =12.6, 5.6 Hz, 1H), 1.81 (dd, J = 2.6, 1.1 Hz, 6H), 1.26 - 1.22 (m, 5H), 1.09(s, 3H).

[0107] HPLC / MS (APCI+): 432 (M + 1), C 22 H 25 O4NS2 calculated for 431.12250.

[0108] MS (EI): 431(M + ), 386, 352, 334, 306, 264, 233, 189, 135, 119, 91,55.

[0109] Example 11

[0110] Preparation of astaxanthin (I-b)

[0111] Under nitrogen protection, 40 ml of dichloromethane, 1.71 g (0.010 mol) of C10-dialdehyde (V), and 20.35 g (0.023 mol) of C15-BTS (Ⅳ, X=OH) were added sequentially to a stirred 250 ml three-necked round-bottom flask. 4.50 g (0.025 mol) of sodium methoxide-methanol solution was slowly added dropwise at 40 °C. After the addition was complete, the reaction temperature was maintained and the reaction continued. The liquid phase was monitored to track the reaction progress. After the reaction was complete, 100 ml of saturated ammonium chloride aqueous solution was added. The mixture was transferred to a separatory apparatus and allowed to stand for separation. The organic phase was separated, washed once with 100 ml of saturated brine, dried with dry sodium sulfate, filtered, and the dichloromethane was recovered under reduced pressure to obtain 21.23 g of crude astaxanthin (Ⅰ-b) (purity 22%, yield of C10-dialdehyde (V) 81%).

[0112] The data obtained after sampling and purification are as follows:

[0113] UV (MeOH): λmax = 473nm.

[0114] IR (KBr): 3454, 2962, 2929, 2868, 2247, 1654, 1550, 1438, 1267, 1074,1037, 960, 914, 727.

[0115] 1 H NMR (400 MHz, CDCl3) δ 6.76 - 6.52 (m, 4H), 6.52 - 6.35 (m, 4H), 6.36 - 6.14 (m, 6H), 4.32 (dd, J = 13.9, 5.6 Hz, 2H), 3.69 (s, 2H), 2.15 (dd,J = 12.7, 5.7 Hz, 2H), 1.99 (d, J = 3.9 Hz, 12H), 1.94 (s, 6H), 1.81 (t, J =13.2 Hz, 2H), 1.32 (s, 6H), 1.21 (s, 6H).

[0116] HPLC / MS (APCI+): 597 (M + 1), C 40 H 52 O4 was calculated for 596.38656.

[0117] MS (EI): 596 (M + , 100%), 563, 504, 490, 443, 389, 377, 297, 263, 197,147, 119, 91, 55.

[0118] Example 12

[0119] Preparation of C15-BT(Ⅲ, X=OH)

[0120] Under nitrogen protection, 9.65 g (0.025 mol) of C15-ol (II), 30 ml of xylene, 5.66 g (0.033 mol) of 2-mercaptobenzothiazole (MBT), 0.12 g (0.00025 mol) of trioctylmethylammonium sulfate and 0.15 g (0.0025 mol) of acetic acid were added sequentially to a stirred 100 ml three-necked round-bottom flask. The reaction was carried out at 45 °C for 48 hours, and the reaction progress was monitored by liquid chromatography. After the raw materials were completely converted, 20 ml of water was added, and the mixture was transferred to a separatory apparatus to stand and separate into layers. The organic phase was washed once with 50 ml of water, and dichloromethane was recovered under reduced pressure to obtain 17.22 g of crude C15-BT(III, X=OH) (purity 48%, yield 83%).

[0121] Example 13

[0122] Preparation of C15-BT(Ⅲ, X=OH)

[0123] Under nitrogen protection, 9.65 g (0.025 mol) of C15-ol (II), 30 mL of dichloromethane, 5.68 g (0.033 mol) of 2-mercaptobenzothiazole (MBT), and 3.01 g (0.050 mol) of acetic acid were added sequentially to a stirred 100 mL three-necked round-bottom flask. The reaction was carried out at 40 °C, and the reaction progress was monitored using a liquid phase. No product was detected after 48 hours of reaction. The results indicate that this step of the reaction cannot occur without the addition of catalysts such as trioctylmethylammonium sulfate.

[0124] Example 14

[0125] Preparation of C15-BTS(Ⅳ, X=OH)

[0126] Under nitrogen protection, 13.59 g (0.02 mol) of C15-BT(Ⅲ, X=OH), 30 ml of ethyl acetate, and 0.10 g (0.0002 mol) of trioctylmethylammonium sulfate were added sequentially to a stirred 100 ml three-necked round-bottom flask; 6.18 g of other solutions were also added. 0.050 mol of hydrogen peroxide was added to 0.06 g (0.00020 mol) of sodium tungstate and stirred until homogeneous. The solution was then slowly added dropwise to the reaction mixture at 0 °C, with the reaction temperature controlled to not exceed 5 °C throughout the process. After the addition was complete, the reaction temperature was maintained and the reaction continued. The liquid phase was used to monitor the reaction progress. After the reaction was completed, 30 g of a prepared 10 wt% sodium bisulfite solution was added and stirred for 0.5 h. The mixture was then transferred to a separatory apparatus and allowed to stand for separation. The aqueous phase was extracted twice with 50 ml of ethyl acetate and combined with the aqueous phase. The aqueous phase was then washed once with 100 ml of saturated brine. The organic phase was separated, dried with dry sodium sulfate, filtered, and dichloromethane was recovered under reduced pressure to obtain 15.23 g of crude C15-BTS(Ⅳ, X=OH) (purity 45%, yield 81%).

[0127] Example 15

[0128] Preparation of C15-BTS(Ⅳ, X=OH)

[0129] Under nitrogen protection, 6.80 g (0.01 mol) of C15-BT(Ⅲ, X=OH) and 30 ml of dichloromethane were added sequentially to a stirred 100 ml three-necked round-bottom flask. Separately, 3.71 g (0.030 mol) of hydrogen peroxide was added to 0.06 g (0.00020 mol) of sodium tungstate, and after thorough mixing, the solution was slowly added dropwise to the reaction mixture at 0 °C. The reaction temperature was controlled to not exceed 5 °C throughout the process. After the addition was complete, the reaction temperature was maintained and the reaction was continued. The reaction progress was monitored using a liquid phase analyzer. After 24 hours of reaction, no product was detected. The results indicate that without the addition of catalysts such as trioctylmethylammonium sulfate, this step of the reaction either does not occur or proceeds extremely slowly.

[0130] Example 16

[0131] Preparation of astaxanthin (I-b)

[0132] Under nitrogen protection, 60 ml of dichloromethane, 1.70 g (0.010 mol) of C10-dialdehyde (V), and 21.89 g (0.024 mol) of C15-BTS (Ⅳ, X=OH) were added sequentially to a stirred 250 ml three-necked round-bottom flask. 25 ml (0.025 mol) of potassium tert-butoxide-tert-butanol solution was slowly added dropwise at 40 °C. After the addition was complete, the reaction temperature was maintained and the reaction continued. The liquid phase was monitored to track the reaction progress. After the reaction was complete, 100 ml of saturated ammonium chloride aqueous solution was added. The mixture was transferred to a separatory apparatus and allowed to stand for separation. The organic phase was separated, washed once with 100 ml of saturated brine, dried with dry sodium sulfate, filtered, and the dichloromethane was recovered under reduced pressure to obtain 22.20 g of crude astaxanthin (Ⅰ-b) (purity 21%, yield of C10-dialdehyde (V) 78%).

Claims

1. A method for preparing oxygen-containing carotenoids, characterized in that, Includes the following steps: (1) Preparation of C15-BT(Ⅲ): Under the protection of an inert gas, C15-alcohol(Ⅱ), 2-mercaptobenzothiazole (MBT), solvent, acid and catalyst were mixed and stirred to obtain C15-BT(Ⅲ). (2) Preparation of C15-BTS(Ⅳ): Under the protection of inert gas, C15-BT(Ⅲ) was mixed with solvent evenly, catalyst A was added, and solution 1 was prepared; oxidant was taken separately, catalyst B was added and stirred evenly, and then added dropwise to solution 1. After the addition was completed, the reaction was carried out to obtain C15-BTS(Ⅳ). (3) Preparation of product (I): Under the protection of inert gas, C15-BTS (IV) and C10-dialdehyde (V) are mixed evenly with solvent, and alkali is added to carry out the reaction to obtain the oxygen-containing carotenoid (I). The reaction formula is as follows: 。 2. The method for preparing oxygenated carotenoids according to claim 1, characterized in that, In step (1), the C15-alcohol (II) is the corresponding C15-tertiary alcohol, C15-primary alcohol, or a mixture of the two; The molar ratio of 2-mercaptobenzothiazole (MBT) to C15-ol (II) is 1.0 to 3.0:

1.

3. The method for preparing oxygenated carotenoids according to claim 1, characterized in that, In step (1), the solvent is one or more of methanol, ethanol, isopropanol, n-butanol, tert-butanol, toluene, xylene, cyclopentyl methyl ether, ethyl acetate, dichloromethane, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, or N,N-dimethylformamide.

4. The method for preparing oxygenated carotenoids according to claim 1, characterized in that, In step (1), the acid is one or more of formic acid, acetic acid, hydrochloric acid, phosphoric acid, or sulfuric acid; The molar ratio of the acid to C15-ol (II) is 0.01 to 2.0:

1.

5. The method for preparing oxygenated carotenoids according to claim 1, characterized in that, In step (1), the catalyst is a quaternary ammonium salt compound, including one or more of trioctylmethylammonium sulfate, tetrabutylammonium chloride, tetrabutylammonium bromide or tetrabutylammonium iodide; The molar ratio of the catalyst to C15-ol(II) is 0.01 to 0.5:

1.

6. The method for preparing oxygenated carotenoids according to claim 1, characterized in that, In step (2), the solvent is one or more of methanol, ethanol, ethylene glycol, isopropanol, n-butanol, tert-butanol, toluene, xylene, cyclopentyl methyl ether, ethyl acetate, dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran, or N,N-dimethylformamide.

7. The method for preparing oxygenated carotenoids according to claim 1, characterized in that, In step (2), the catalyst A is a quaternary ammonium salt compound, including one or more of trioctylmethylammonium sulfate, tetrabutylammonium chloride, tetrabutylammonium bromide or tetrabutylammonium iodide; The molar ratio of catalyst A to C15-BT(Ⅲ) is 0.01 to 0.5:1; The oxidant is one or more of hydrogen peroxide, urea peroxide, peroxyformic acid, peracetic acid, tert-butyl hydroperoxide, or m-chloroperoxybenzoic acid. The molar ratio of the oxidant to C15-BT(Ⅲ) is 2.0 to 6.0:

1.

8. The method for preparing oxygenated carotenoids according to claim 1, characterized in that, In step (2), the catalyst B is one or more of sodium acetate, sodium tungstate, ammonium heptamolybdate, or 2,2,6,6-tetramethylpiperidine oxide; The molar ratio of catalyst B to C15-BT(Ⅲ) is 0.01 to 0.5:

1.

9. The method for preparing oxygenated carotenoids according to claim 1, characterized in that, In step (3), the molar ratio of C15-BTS(Ⅳ) to C10-dialdehyde(Ⅴ) is 2.0 to 5.0:1; The solvent is one or more of methanol, ethanol, isopropanol, n-butanol, tert-butanol, toluene, xylene, cyclopentyl methyl ether, ethyl acetate, dichloromethane, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, or N,N-dimethylformamide.

10. The method for preparing oxygenated carotenoids according to claim 1, characterized in that, In step (3), the alkali is one or more of sodium hydroxide, potassium hydroxide, sodium methoxide, potassium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), sodium bis(trimethylsilyl)amino, lithium bis(trimethylsilyl)amino, lithium diisopropylamino, or n-butyllithium; The molar ratio of the amount of alkali used in step (3) to C10-dialdehyde (V) is 2.0 to 5.0:1.

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