CN115557958A - A method for preparing biotin intermediate optically active lactone - Google Patents

Abstract

The invention provides a method for preparing biotin intermediate optically active lactone, which comprises the following steps of 1) reducing biotin intermediate imide by using sodium borohydride to obtain an imide reduced product, wherein the sodium borohydride is added in batches; 2) Purifying the imide reduced product obtained in the step 1); 3) Reducing and ring-opening the imide reduced product purified in the step 2) by using sodium borohydride to obtain biotin intermediate amine alcohol, wherein the sodium borohydride is added in batches; 4) And hydrolyzing the biotin intermediate amino alcohol with acid to obtain biotin intermediate optically active lactone. According to the invention, imide is reduced to obtain a selective reduction product, chiral impurities are removed through crystallization and refining to obtain a pure reduction product, the reduction product is continuously reduced to obtain the aminoalcohol, the aminol can be directly hydrolyzed without separation and purification to obtain the optically active lactone (IV) with qualified optical purity, the total yield is improved, the operation is simplified, waste materials are reduced, and the optically active lactone (IV) has great industrial value.

Description

A method for preparing biotin intermediate optically active lactone

technical field

The invention relates to the field of vitamin intermediates, in particular to a method for preparing optically active lactones of biotin intermediates.

Background technique

(+)-Biotin, also known as vitamin H or coenzyme R, chemically named (3aS,4S,6aR)-hexahydro-2-oxo-1H-thieno[3,4-d]imidazole-4 -Valeric acid, widely distributed in animal and plant tissues, has been isolated from liver extract and egg yolk, is a component of a variety of carboxylase prosthetic groups, and is a necessary substance for the growth and development of animals and plants.

Since the first synthesis of d-biotin by Merck in 1944, there are now more than 40 chemical total synthesis methods of biotin. The starting materials include L-cysteine, L-cysteine, fumaric acid, d-glucose, d-arabinose, pimelic acid, etc. Among them, the most classic one is the Goldberg-Sterbach process of Roche Company, which realizes for the first time The industrialized production of biotin has been eliminated, and most of the industrialized processes now come from the improvement of the process. A key intermediate of this route is photoactive lactone (Ⅳ), which reacts with potassium thioacetate in DMF to maintain configuration and obtain photoactive thiolactone (Ⅴ) in higher yield. Using photoactive thiolactone, d-biotin can be directly synthesized through several steps, and the synthetic route is as follows:

Therefore, as a key intermediate, the synthesis of optically active lactone (Ⅳ) is extremely important.

In 1975, Sumitomo Company invented an asymmetric synthesis method of optically active lactone (Ⅳ): meso diacid was first combined with (S, S)-(+)-threo-1-(p-nitrophenyl )-2-amino-1,3-propanediol (the by-product of the antibiotic chloramphenicol) was reacted to obtain imide (Ⅱ), which was reduced by NaBH ₄ and ring-opened to obtain amine alcohol (ⅢA), and then recrystallized to remove its optical The by-product (ⅢB); then the amino alcohol (ⅢA) is acid-hydrolyzed to obtain the desired optically active lactone (Ⅳ), and the yield after recrystallization is 65%, and the ee value reaches 98%. Wherein the key to controlling the optical purity of the lactone is the purity of the aminoalcohol (ⅢA), and the synthetic route is as follows:

The two carbonyl groups of imide (II) are asymmetrically reduced due to different chemical environments, and while producing the target product (IIIA), a small amount of another diastereoisomer (IIIB ). If not separated, the optical isomer impurity (IVB) obtained by the hydrolysis of the diastereoisomer (ⅢB) will always be brought into the final product, affecting the content of product biotin; if separated and refined, the yield will be reduced. significantly reduce.

Contents of the invention

The object of the present invention is to provide a kind of method for preparing biotin intermediate optically active lactone, described method comprises the steps:

1) Reducing the biotin intermediate imide shown in formula (II) with sodium borohydride to obtain the imide reduction product shown in formula (I), wherein sodium borohydride is added in batches;

2) Purifying the reduced imide obtained in step 1);

3) The purified imide reduction product in step 2) is reduced and opened with sodium borohydride to obtain the biotin intermediate amine alcohol shown in formula (III), wherein sodium borohydride is added in batches;

4) hydrolyzing the biotin intermediate amine alcohol with acid to obtain the biotin intermediate optically active lactone shown in formula (IV);

Wherein R* is chiral amine, Bn is benzyl.

After an in-depth analysis of the asymmetric reduction reaction of the imide (II, the following structural formula), the present invention believes that the selective reduction of the 4- and 6-carbonyl groups of the imide by NaBH ₄ is mainly due to the influence of steric hindrance. The carbonyl at position 6 is preferentially reduced to alcohol due to the small steric hindrance.

The imide reduction product represented by formula (I), its chemical name is (3aS, 6aR)-1,3-dibenzyl-5-[(1S,2S)-(+)-threo-1'- Hydroxymethyl-2'-p-nitrophenyl-2'-hydroxy-ethyl]-hexahydro-1H-pyrrolo[3,4-d]imidazole-6-hydroxy-2,4-dione:

Wherein Bn is benzyl.

In the preferred technical scheme of the method of the present invention, preferably, R* is the right amine, (1S,2S)-(+)-threo-1-(p-nitrophenyl)-2-amino-1,3 - Propylene glycol.

In the preferred technical scheme of the method of the present invention, preferably, in step 1), the molar ratio of the amount of sodium borohydride to the amount of the biotin intermediate imide is 0.3-0.5:1, and the volume of the aqueous ethanol solvent The ratio of the dosage to the weight dosage of the biotin intermediate imide is 3-6:1, and the reaction is carried out in a water-containing ethanol solvent at -15-0°C.

In a preferred technical solution of the method of the present invention, preferably, in step 2), the purification of the reduced imide is recrystallization purification.

In the preferred technical scheme of the method of the present invention, preferably, in step 3), the molar ratio of the amount of sodium borohydride to the amount of the purified imide reduced product is 2.0-2.2:1, and the volume of the aqueous ethanol The ratio of the amount used to the weight amount of the imide reducing product is 3-6:1, and the reaction is carried out in a water-containing ethanol solvent at 5-10°C.

In the preferred technical solution of the method of the present invention, preferably, in step 3), the biotin intermediate amine alcohol can be further purified.

In a preferred technical solution of the method of the present invention, preferably, the hydrolysis temperature is 90-100° C., and the acid is selected from one of acetic acid, hydrochloric acid, and sulfuric acid.

In the preferred technical solution of the method of the present invention, preferably, in step 1) and step 3), the aqueous ethanol solvent is 95% ethanol aqueous solution.

In a preferred technical solution of the method of the present invention, preferably, the solvent for the recrystallization is methanol, ethanol or isopropanol.

In the preferred technical solution of the method of the present invention, preferably, in step 4), after hydrolysis, thin-layer detection is carried out, and after completion, stop heating, cool to room temperature, and neutralize to neutrality with lye; then use organic solvent Extraction, washing with water twice, drying, recovering the solvent under reduced pressure, recrystallization to obtain white crystalline powder lactone (IV); the lye is selected from one of the aqueous solutions of sodium hydroxide, sodium carbonate and sodium bicarbonate ; The organic solvent is selected from one of toluene, normal hexane, hexanaphthene, ether, and methylene chloride.

In the present invention, the selective reduction product is obtained by reducing the imide, and the chiral impurities are removed by crystallization and purification to obtain a pure reduction product, which can be further reduced to obtain an amino alcohol, which can be directly hydrolyzed without separation and purification to obtain an optical The optically active lactone (Ⅳ) with qualified purity has improved total yield, simplified operation and reduced waste, and has great industrial value.

Description of drawings

Fig. 1A is the ¹ H-NMR spectrum of imide reduction product (I);

Fig. 1B is the ¹³ C-NMR spectrum of imide reduction product (I);

Fig. 2A is the infrared spectrogram of biotin intermediate optically active lactone (IV);

Figure 2B is the ¹ H-NMR spectrum of the biotin intermediate optically active lactone (IV);

Figure 2C is the ¹³ C-NMR spectrum of the biotin intermediate optically active lactone (IV);

Figure 2D is the DEPT135 spectrum of the biotin intermediate optically active lactone (Ⅳ);

Fig. 3 is a three-dimensional structure diagram of the crystal structure determination of the imide reduction product (I) by the Analysis and Testing Center of Zhejiang University.

detailed description

The detailed description is as follows with reference to the attached preferred embodiments, and the attached preferred embodiments are only used to illustrate the technical solutions of the present invention, not to limit the present invention.

The analytical instruments and equipment used in the various embodiments of the present invention are: nuclear magnetic resonance instrument, AVANCE DMX Ⅱ Ⅰ 400M (TMS internal standard, Bruker Company); infrared spectrometer, NICOLET 360FT-IR.

Embodiment 1: the preparation of imide reduction product (I)

Put 21.2g of imide (0.04mol) into a three-necked flask, add 80ml of solvent 95% ethanol aqueous solution, and add 0.65g of sodium borohydride (0.017mol) in batches at -10°C, and add it in about 1 hour. React at 15-0°C for about 1 hour. Thin-layer chromatography detects that the reaction is complete. Neutralize to neutral with acetic acid. After evaporating the solvent, add 50 ml of isopropanol, heat to dissolve, cool to 5°C to crystallize, and precipitate a large amount of white solid. Suction filtration and drying yielded 18.9 g of the product, with a molar yield of 88.7%, and mp of 96-97°C.

¹ H NMR (400MHz, DMSO) δ8.181 (d, J = 8.4Hz, 2H), 7.621 (d, J = 8.4Hz, 2H), 7.179–7.380 (m, 10H), 6.675 (d, J = 6.0 Hz,1H),6.159–6.171(m,1H),5.209–5.236(m,1H),5.063–5.090(m,1H),4.815–4.891(m,2H),4.662(d,J＝15.2Hz, 1H), 4.164(d, J=15.2Hz, 1H), 3.906–4.027(m, 3H), 3.617–3.677(m, 2H), 3.522–3.577(m, 1H), as shown in Fig. 1A.

¹³ C NMR(101MHz,DMSO)δ170.40,159.01,150.40,146.66,137.39,136.91,128.61,128.49,127.98,127.92,127.82,127.35,127.25,123.07,79.21,70.15,60.23,58.37,55.17,52.13,46.38, 45.35, as shown in Figure 1B.

Example 2: Continued reduction and hydrolysis of imide reducing product (I) to prepare lactone

Add 80ml of 95% aqueous ethanol to a 250ml three-necked flask, stir in a cold bath at 5°C, add 10.6g (0.020mol) of the reduced product prepared in the previous example (Example 1), and start adding 1.6g in batches after stirring for a few minutes (0.042mol) sodium borohydride, added in about half an hour, the reduction was insoluble at the beginning, when the batch was added, the solution became clear, continued to insulate and stir for about 48 hours, after the TLC detection reaction was completed, neutralized with acetic acid until Neutral, distill off the solvent to obtain the crude product. Add 59g (0.12mol) of 20% sulfuric acid aqueous solution to the bottle, magnetically stir and reflux at 90-100°C for 4h, after the TLC detection reaction is completed, stop heating, cool to room temperature, and use dilute lye (10% sodium hydroxide aqueous solution) neutralized to neutral, then extracted three times with 150ml of dichloromethane, combined the organic layers, washed twice with water, dried with 2g of anhydrous sodium sulfate, recovered the solvent under reduced pressure, and recrystallized with 95% aqueous ethanol. 5.8 g of white solid powder was obtained, the molar yield was 90.0%, the mp was 116-117°C, the specific rotation [α] _D ²⁰ =+59.4°, and the ee value was 98.9%.

In the above two-step reaction, the imide is first reduced to the reduced product, and after refining, reduction ring-opening, hydrolysis and recrystallization, the product lactone meeting the content requirement is obtained, and the total molar yield of the two steps is 79.8%.

Confirmation of structure:

IR: 3033.75 (Ar-H), 1769.88 (C=O, ester), 1700.57 (C=O, ketone), 1443.71 (C=C, benzene), 1211.33 (C-O, ester), 697.62 (δAr-H ), as shown in Figure 2A.

¹ HNMR (CDCl ₃ ): 7.252～7.400 (m, 10H, benzene ring H), 5.062 (d, 1H, J=14.8H _Z , C7H), 4.646 (d, 1H, J=15.2H _Z , C8H), _{( _} d, 1H, J=8.8H _Z , C6aH), as shown in Fig. 2B.

¹³ CNMR (CDCl ₃ ): 172.76 (C4), 158.12 (C2), 135.94 (C10), 135.83 (C9), 127.80～128.94 (benzene ring C except 9, 10), 70.04 (C6), 54.33 (C6a ), 52.39(C3a), 46.83(C7), 45.15(C8), as shown in Figure 2C.

DEPT (θ=135°): 127.80~128.94, 70.03(D), 54.33, 52.39, 46.827(D), 45.149(D), as shown in Fig. 2D.

Cultivation of single crystals: Put a little of the lactone crystal powder obtained above in a vial, dissolve it with ethanol, seal it with filter paper, and leave it for five weeks to precipitate colorless transparent crystals. The crystal structure was determined by the Analysis and Testing Center of Zhejiang University. The three-dimensional structure is shown in Figure 3.

Example 3: Continued reduction and hydrolysis of imide reducing product (I) to prepare lactone

According to the method of the above example (Example 2), the imide reduction product (I) prepared in Example 1 was further reduced and ring-opened to obtain the crude product of aminoalcohol (III). Recrystallize with 50ml of isopropanol to obtain 10.1g of white solid. Add 12g (0.12mol) of 37% hydrochloric acid to the bottle, magnetically stir and reflux for 4 hours, stop heating after the TLC reaction is completed, cool to room temperature, neutralize with dilute lye (10% sodium hydroxide aqueous solution) to neutral , and then extracted three times with 150ml of dichloromethane, combined the organic layers, washed twice with water, dried with 2g of anhydrous sodium sulfate, recovered the solvent under reduced pressure, and recrystallized with 95% ethanol. 5.5 g of white solid powder was obtained, yield 85.3%, mp 116-117°C, specific rotation [α] _D ²⁰ =+60.0°, ee value 100%.

In Example 1 and Example 3, the imide was first reduced to the reduced product, and after refining, reducing ring opening, refining, hydrolysis, and recrystallization, the product lactone meeting the content requirements was obtained, and the total molar yield in 2 steps was 75.7%. Confirmation of structure:

IR: 3033.75 (Ar-H), 1769.88 (C=O, ester), 1700.57 (C=O, ketone), 1443.71 (C=C, benzene), 1211.33 (C-O, ester), 697.62 (δAr-H ), as shown in Figure 2A.

¹ HNMR (CDCl ₃ ): 7.252～7.400 (m, 10H, benzene ring H), 5.062 (d, 1H, J=14.8H _Z , C7H), 4.646 (d, 1H, J=15.2H _Z , C8H), _{( _} d, 1H, J=8.8H _Z , C6aH), as shown in Fig. 2B.

¹³ CNMR (CDCl ₃ ): 172.76 (C4), 158.12 (C2), 135.94 (C10), 135.83 (C9), 127.80～128.94 (benzene ring C except 9, 10), 70.04 (C6), 54.33 (C6a ), 52.39 (C3a), 46.83 (C7), 45.15 (C8), as shown in Figure 2C.

DEPT (θ=135°): 127.80~128.94, 70.03(D), 54.33, 52.39, 46.827(D), 45.149(D), as shown in Fig. 2D.

Cultivation of single crystals: Put a little of the lactone crystal powder obtained above in a vial, dissolve it with ethanol, seal it with filter paper, and leave it for five weeks to precipitate colorless transparent crystals. The crystal structure was determined by the Analysis and Testing Center of Zhejiang University. The three-dimensional structure is shown in Figure 3.

Comparative Example 1: Preparation of Lactone by Direct Hydrolysis of Imide Reduction

Add 100ml of 95% ethanol aqueous solution to a 250ml three-neck flask, stir in a cold bath at -10°C, add 21.2g (0.04mol) of imide, stir for a few minutes, then add 3.8g (0.10mol) of sodium borohydride in batches , The addition was completed in about half an hour, and the TLC reaction proceeded. The reaction solution was moved to room temperature, and stirred magnetically for 48 hours. After the reaction was detected by TLC, the acetic acid was neutralized to neutral, and the solvent was evaporated under reduced pressure. The obtained solid was added with 20% sulfuric acid 98g (0.2mol), and magnetically stirred and refluxed for 4h. After the layer detection reaction, stop heating, let it cool to room temperature, neutralize to neutral with dilute lye, then extract three times with 150ml of dichloromethane, combine the organic layers, wash twice with water, and dry with anhydrous sodium sulfate , after recovering the solvent under reduced pressure, recrystallize with 95% ethanol to obtain 10.9g of white crystalline powder, the total yield is 84.6%, mp116～118°C, specific rotation [α] _D ²⁰ =+50.2°, ee value 83.7% . Its optical purity does not meet the requirements.

Its nuclear magnetic data is consistent with embodiment 2.

Comparative Example 2: Reduction of imide to amino alcohol, hydrolysis of amino alcohol to prepare lactone after recrystallization

Add 184ml of ethanol and 16ml of water into a 250ml three-neck flask, stir in a cold bath at -10°C, add 42.4g (0.08mol) of imide, and start adding 7.6g (0.21mol) of sodium borohydride in batches after stirring for a few minutes. The addition was completed in about half an hour, and the TLC reaction proceeded. The reaction solution was moved to room temperature, and stirred by magnetic force for 48 hours. After the reaction was detected by TLC, the acetic acid was neutralized to neutrality. After the solvent was evaporated, 50ml of isopropanol was used to recrystallize to obtain 26.2g of white solid, which was hydrolyzed according to the above method, 95 % ethanol aqueous solution recrystallized to obtain 15.0 g of white crystalline powder, total yield 58.0%, mp 116-117°C, specific rotation [α] _D ²⁰ =+60.0°, ee value 100%.

Its nuclear magnetic data is consistent with embodiment 2.

After the method of the present invention is compared with the methods of Comparative Example 1 and Comparative Example 2, it can be concluded that the method of the present invention can not only obtain the product whose content meets the requirements, but also ensure a higher yield, which is of great industrial value.

It should be declared that the above summary of the invention and specific implementation methods are intended to prove the practical application of the technical solutions provided by the present invention, and should not be interpreted as limiting the protection scope of the present invention.

Claims (10)

1. A method for preparing biotin intermediate optically active lactone, said method comprising the steps of: 1) Reducing the biotin intermediate imide shown in formula (II) with sodium borohydride to obtain the imide reduction product shown in formula (I), wherein sodium borohydride is added in batches; 2) Purifying the reduced imide obtained in step 1); 3) The purified imide reduction product in step 2) is reduced and opened with sodium borohydride to obtain the biotin intermediate amine alcohol shown in formula (III), wherein sodium borohydride is added in batches; 4) hydrolyzing the biotin intermediate amine alcohol with acid to obtain the biotin intermediate optically active lactone shown in formula (IV);

Wherein R* is chiral amine, Bn is benzyl. 2. The preparation method according to claim 1, wherein R* is the right amine, (1S,2S)-(+)-threo-1-(p-nitrophenyl)-2-amino-1 ,3-propanediol. 3. The method according to claim 1 or 2, characterized in that, in step 1), the molar ratio of the amount of sodium borohydride to the amount of the biotin intermediate imide is 0.3-0.5:1, and the water-containing The ratio of the volume of the ethanol solvent to the weight of the biotin intermediate imide is 3-6:1, and the reaction is carried out in the aqueous ethanol solvent at -15-0°C. 4. The method according to claim 1 or 2, characterized in that, in step 2), the purification of the reduced imide is recrystallization purification. 5. The method according to claim 1 or 2, characterized in that, in step 3), the molar ratio of the amount of sodium borohydride to the amount of the purified imide reduced product is 2.0-2.2: 1, the The ratio of the volume of ethanol in water to the weight of the imide reducing product is 3-6:1, and the reaction is carried out in a water-containing ethanol solvent at 5-10°C. 6. The method according to claim 1, 2 or 5, characterized in that, in step 3), the biotin intermediate amine alcohol can be further purified. 7. The method according to claim 1, characterized in that, in step 4), the temperature of the hydrolysis is 90-100° C., and the acid is selected from one of acetic acid, hydrochloric acid and sulfuric acid. 8. The method according to claim 3 or 5, characterized in that, in step 1) and step 3), the aqueous ethanol solvent is 95% aqueous ethanol. 9. The method according to claim 1 or 2, characterized in that, the solvent for the recrystallization is methanol, ethanol or isopropanol. 10. The method according to claim 1, 2 or 7, characterized in that, in step 4), after the hydrolysis, thin-layer detection is carried out, and after completion, heating is stopped, cooled to room temperature, neutralized to neutral with lye Then extract with organic solvent, after washing twice, dry, after decompression recovery solvent, recrystallization obtains white crystalline powder lactone (IV); Described lye is selected from sodium hydroxide, sodium carbonate, sodium bicarbonate One of the aqueous solutions; the organic solvent is selected from one of toluene, n-hexane, cyclohexane, ether, and dichloromethane.

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