CN102757399B - Preparation method of aliskiren intermediate - Google Patents

Abstract

The invention discloses a preparation method of Alikren intermediate shown as formula IV, which comprises the following steps: under the protection of an inert gas, in a dry organic solvent, compound II and compound III in titanium tetrachloride and dry Under the action of DIPEA, the following reaction can be carried out; wherein, Z is Cl, Br or I; R ¹ , R ² and R ⁵ are independently H, C ₁ ~ C ₃ linear or branched chain alkyl, C ₁ -C ₃ straight-chain or branched alkoxy, C ₁ -C ₃ straight-chain or branched alkyl substituted by C ₁ -C ₃ straight-chain or branched alkoxy, or, C ₁ C ₁ -C ₆ alkoxy substituted by -C ₆ alkoxy; R ³ is C ₁ -C ₄ linear or branched chain alkyl; R ⁴ is benzyl or benzyl with substituents on the benzene ring base; R ⁶ is O, S or HN. The invention greatly improves the yield of the reaction, reduces the cost of the reaction and improves the efficiency of the reaction. Therefore, the invention is suitable for large-scale industrial production and has broad application prospects.

Description

A kind of preparation method of Alikren intermediate

technical field

The invention relates to a method for preparing an Aliskiren intermediate.

Background technique

Cardiovascular disease, including high blood pressure, ranks first among the diseases that cause death in the world. At present, the incidence of hypertensive diseases in my country is about 23.3%, and the number of patients has exceeded 160 million, and it is increasing year by year. There are about 3.5 million new hypertensive patients every year. Every year, cardiovascular and cerebrovascular diseases caused by hypertension More than 2.6 million people died from the disease. According to statistics, the drugs currently used to treat hypertension can only control the condition of 25% of hypertensive patients. Therefore, many pharmaceutical companies and scientific research institutes at home and abroad are competing to research and develop drugs that can effectively prevent and treat cardiovascular diseases such as hypertension.

Aliskiren (Aliskiren) is a second-generation renin inhibitor that acts on the renin-angiotensin-aldosterone system (RAAS), and is the first new oral non-peptide renin activity inhibitor for the treatment of primary Safe and effective for hypertensive disorders. On March 31, 2007, Alikren tablets were first approved by the US FDA for the treatment of hypertension, chronic kidney disease, congestive heart failure and other diseases. They were subsequently launched in Germany and the United Kingdom. In 2008, they were launched in Ireland, Iceland and Norway also received separate approvals. In 2009, the sales of Novartis Alikren reached 300 million US dollars, a year-on-year increase of 101%, and its sales in 2014 are expected to reach 1.2 billion US dollars.

In addition to Aliskiren tablets, a variety of Aliskiren compound preparations have also been approved for marketing, such as Aliskiren-Amlodipine Compound Tablets, Aliskiren-Hydrochlorothiazide Compound Preparations, Aliskiren-Valsartan Compound preparations, Aliskiren-Ramipril compound preparations and Aliskiren-Shuangke compound preparations are favored by many pharmaceutical companies because of their good curative effect and economic benefits.

Researchers have conducted extensive and in-depth research on the chemical synthesis of Aliklen. In the existing synthetic methods, each route has its unique features. More representative is the synthesis method reported by Goschke et al. in 1998. The method takes 3-hydroxyl-4-methoxybenzaldehyde as starting material, and compound A is obtained through a series of reactions; The Grignard reagent is reacted, and the corresponding alcohol is obtained through hydrogenolysis; after the alcohol hydroxyl is oxidized into a carboxyl group, it is condensed with the third fragment primary amine to generate an amide; finally, the acetonylidene and tert-butoxycarbonyl groups are removed in dilute hydrochloric acid ( Boc) protecting group to obtain the hydrochloride salt of the target molecule.

In the above synthetic route, the second fragment (2S)-bromomethyl-3-methyl-butyl benzyl ether involved is an important intermediate for the synthesis of Alikren, which plays a role in the introduction of chiral carbon atoms in the Alikren molecule. played a vital role.

In 2003, Goeschke, Richard; Stutz, Stefan; Heinzelmann, Walter; Helvetica Chimica Acta, 2003, vol.86, P2848-2870 reported (2S)-bromomethyl-3-methyl-butylbenzyl ether as shown below synthetic method.

The above method introduces a chiral center through the asymmetric alkylation of the carbonyl α position induced by the Evans prosthetic group, and then removes the Evans prosthetic group under the action of lithium hydroxide and hydrogen peroxide, and the obtained carboxylic acid is reduced to an alcohol with sodium borohydride, and finally The target compound can be obtained by bromination under the action of N-bromosuccinimide (NBS) and triphenylphosphine. The total yield of this synthetic route is 29.6%. Among them, in the first step of asymmetric alkylation reaction, the solvents and reagents used are not anhydrous, and the reaction is not carried out under anhydrous conditions. The reaction yield is only 50%. %. In addition, the triphenylphosphine oxide produced during the bromination reaction is not easy to remove, and the product needs to be purified by column chromatography. The post-treatment operation is more complicated, the product loss is more, and the efficiency is low. Moreover, the price of the brominated reagent N-bromosuccinimide is relatively high, resulting in a relatively high cost of this synthetic method.

In 2005, Dong, Hua; Zhang, Zhi-Liu; Tetrahedron Letters, 2005, vol.46, P6337-6340 reported the following synthetic route:

The difference between this synthetic route and the aforementioned synthetic route of Goeschke, Richard et al. is that when reducing carboxylic acid to alcohol, the reducing agent used is LiAlH ₄ . Due to the high price of LiAlH ₄ , the operation of the experiment and post-treatment process is more complicated, and the environmental pollution is greater. There are certain safety hazards when used in industrial production. Moreover, the synthesis efficiency of this route is also low, and the total yield is only 21.5%.

Contents of the invention

The technical problem to be solved by the present invention is to overcome the low reaction yield and post-treatment operation that exist in the synthetic method of the existing Alikren intermediate (2S)-bromomethyl-3-methyl-butylbenzyl ether. Complicated, high cost, unfavorable for the defects of large-scale industrial production, and a preparation method of oxazolidinone derivatives is provided, which can conveniently prepare the Alikren intermediate (2S)-bromomethyl -3-Methyl-butylbenzyl ether and its derivatives. The method has the advantages of high yield, simple operation and low cost, and is suitable for industrial large-scale production.

Therefore, the present invention relates to a preparation method of oxazolidinone derivatives shown in formula IV, which comprises the following steps: under the protection of an inert gas, in a dry organic solvent, compound II and compound III in titanium tetrachloride With dry N, under the effect of N-diisopropylethylamine (DIPEA), carry out following reaction, get final product;

Wherein, Z is Cl, Br or I.

R ¹ , R ² and R ⁵ are independently H, C ₁ to C ₃ linear or branched alkyl, C ₁ to C ₃ linear or branched alkoxy, C ₁ to C ₃ linear A C ₁ -C ₃ linear or branched chain alkyl group substituted by a chain or branched alkoxy group, or a C ₁ -C ₆ alkoxy group substituted by a C ₁ -C ₆ alkoxy group.

In R ¹ , the C ₁ -C ₃ linear or branched alkyl substituted by C ₁ -C ₃ linear or branched alkoxy is preferably C ₁ -C ₂ linear C ₁ to C ₃ linear or branched chain alkyl substituted by branched alkoxy; in R ¹ , the C ₁ to C ₆ alkoxy substituted by C ₁ to C ₆ alkoxy C ₁ to C ₃ straight or branched alkoxy, methoxypentyloxy, _{methoxyhexyloxy} , _1- Ethoxybut-4-yloxy, ethoxypentyloxy or butoxymethoxy; preferably C ₁ to C ₃ (preferably C ₁ to C ₂ ) straight or branched chain alkane C ₁ -C ₃ linear or branched alkoxy group substituted with oxy group.

In R ² , the C ₁ -C ₃ linear or branched alkyl substituted by C ₁ -C ₃ linear or branched alkoxy is preferably C ₁ -C ₂ linear C ₁ to C ₃ linear or branched chain alkyl substituted by branched alkoxy; in R ² , the C ₁ to C ₆ alkoxy substituted by C ₁ to C ₆ alkoxy C ₁ to C ₃ straight or branched alkoxy, methoxypentyloxy, _{methoxyhexyloxy} , _1- Ethoxybut-4-yloxy, ethoxypentyloxy or butoxymethoxy; preferably C ₁ to C ₃ (preferably C ₁ to C ₂ ) straight or branched chain alkane C ₁ -C ₃ linear or branched alkoxy group substituted with oxy group.

In R ⁵ , the C ₁ -C ₃ linear or branched alkyl substituted by C ₁ -C ₃ linear or branched alkoxy is preferably C ₁ -C ₂ linear C ₁ to C ₃ linear or branched chain alkyl substituted by branched alkoxy; in R ⁵ , the C ₁ to C ₆ alkoxy substituted by C ₁ to C ₆ alkoxy C ₁ to C ₃ straight or branched alkoxy, methoxypentyloxy, _{methoxyhexyloxy} , _1- Ethoxybut-4-yloxy, ethoxypentyloxy or butoxymethoxy; preferably C ₁ to C ₃ (preferably C ₁ to C ₂ ) straight or branched chain alkane C ₁ -C ₃ linear or branched alkoxy group substituted with oxy group.

R ³ is a C ₁ -C ₄ linear or branched alkyl group; preferably isopropyl.

R ⁴ is a benzyl group, or a benzyl group with a substituent on the benzene ring; wherein, the benzyl group with a substituent on the benzene ring is that the benzene ring is replaced by 1 to 3 halogens and C ₁ to C ₃ A benzyl group substituted with a linear or branched alkyl group.

R ⁶ is O, S or HN.

Preferably, ^R1 is H, ^R2 is H, ^R3 is isopropyl, ^R4 is benzyl, ^R5 is H and ^R6 is O.

Wherein, the inert gas may be an inert gas conventionally used in the art, such as nitrogen or argon. The organic solvent can be a conventional solvent for this type of reaction in the art, preferably one of tetrahydrofuran, acetonitrile, methylene chloride, chloroform, dimethyl sulfoxide, dioxane, acetone and butanone Or multiple, more preferably dichloromethane and/or tetrahydrofuran. The amount of the organic solvent can be a conventional amount for this type of reaction in the art; preferably, the volume-to-mass ratio of the organic solvent to compound III is 5-30ml/g; more preferably 8-15ml/g . The amount of the compound II can be the conventional amount of this type of reaction in the art; preferably, the molar ratio of the compound II to the compound III is 1.5:1 to 3:1; more preferably 1.8:1 to 2.2:1. The amount of said titanium tetrachloride can be a conventional amount for this type of reaction in the art; preferably, the molar ratio of said titanium tetrachloride to compound III is 1:1 to 2:1; more preferably 1:1～1.2:1. The amount of said N,N-diisopropylethylamine can be the conventional amount of this type of reaction in the art; preferably, the molar ratio of said N,N-diisopropylethylamine to compound III is 1:1 to 5:1; more preferably 1:1 to 2:1. The temperature of the reaction may be a conventional temperature for this type of reaction in the art, preferably -20-10°C, more preferably -5-5°C. The reaction time is preferably until the completion of the detection reaction, generally 20-48 hours, preferably 24-30 hours.

Preferably, the above-mentioned preparation method comprises the following steps: under the protection of an inert gas, compound III, titanium tetrachloride, N, N-diisopropylethylamine (DIPEA) and compound II are sequentially added to a dry organic solvent, Carry out following reaction, get final product;

Wherein, the definitions of the groups R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and Z are the same as those mentioned above.

Wherein, the type and amount of the organic solvent are the same as previously described. The amounts of titanium tetrachloride, N,N-diisopropylethylamine (DIPEA) and compound II are the same as those mentioned above. The temperature and time of the reaction are the same as previously described.

Preferably, after adding titanium tetrachloride, stir for 5 minutes to 1 hour, preferably 10 to 15 minutes, and then add N,N-diisopropylethylamine.

Preferably, after adding N,N-diisopropylethylamine, stir for 1-4 hours, preferably 1-1.5 hours, and then add compound II.

On the basis of not violating the general knowledge in the field, the above-mentioned preferred technical features in the present invention can be combined arbitrarily to obtain the preferred examples of the present invention.

Unless otherwise specified, the raw materials or reagents described in the present invention are commercially available.

The positive progress effect of the present invention is that: the present invention greatly improves the yield of the reaction, reduces the cost of the reaction, and improves the efficiency of the reaction. Therefore, the invention is suitable for large-scale industrial production and has broad application prospects.

Detailed ways

The present invention is further illustrated below with examples, but the present invention is not limited thereto.

Unless otherwise specified, the raw materials or reagents used in the examples are commercially available.

The room temperature mentioned in the examples all refers to 20-35°C.

In the following examples, compound IIa is ^a compound in which R in the general formula ^II is H, R is H, and Z is Cl; compound IIIa is in the general ^formula III in ^R3 is isopropyl, R4 is benzyl, R ⁵ is H, R ⁶ is the compound of O; compound IVa is the compound IV in which R ¹ is H, R ² is H, R ³ is isopropyl, R ⁴ is benzyl, R ⁵ is H, R ⁶ is the compound of O; compound Va is the compound in which R is H in the general ^formula compound V, R is H, and ^R is the compound ^of isopropyl ^; compound VIa is the compound in which R is H in the general ^formula VI, and R is H, R ³ is a compound of isopropyl; Compound Ia is a compound of general formula I in which R ¹ is H, R ² is H, R ³ is isopropyl, and X is Br.

Example 1 Preparation of Compound IVa

Under the protection of nitrogen, compound IIIa (40.0g, 153.2mmol) was dissolved in 500ml of anhydrous CH ₂ Cl ₂ , cooled to 0°C, and TiCl ₄ (18ml, 163.8mmol) was added dropwise. The solution turned yellow and stirred for 5min; Add N, N-diisopropylethylamine (30ml, 174mmol) dropwise, the reaction solution turns black, and stir for 1 hour; add compound IIa (44ml, 316.8mmol) dropwise, and react at 0°C After 20 hours, the reaction solution gradually turned yellow. Add 200ml of saturated NH ₄ Cl aqueous solution and 320ml of water, stir, separate the layers, extract the aqueous phase with CH ₂ Cl ₂ (70ml×2), combine the organic phases, wash with water and saturated brine in turn, and dry over anhydrous MgSO ₄ . Filtration and concentration under reduced pressure gave an oil (50.2 g, 85.8%), which was recrystallized from n-hexane and petroleum ether to give 46.9 g of a white solid with a yield of 80.1% and an HPLC purity of over 99.0%.

Its structural identification data are as follows:

¹ H NMR (400MHz, CDCl ₃ ): δ7.15-7.35(m, 10H); 4.65-4.8(m, 1H); 4.54(m, 2H); 4.05-4.25(m, 3H); 3.88(t, J=8Hz, 1H); 3.71(dd, J=4, 8Hz, 1H); 3.22(dd, J=2, 13Hz, 1H); 2.61(dd, J=9, 13Hz, 1H); 2.04(m, 1H); 0.96(t, J=7Hz, 6H).

Experimental results under other reaction conditions: (wherein, what serial number is 14 is comparative example)

Example 2 Preparation of Compound IVa

Under the protection of nitrogen, compound IIIa (40.0g, 153.2mmol) was dissolved in 500ml of anhydrous tetrahydrofuran, cooled to 0°C, and TiCl ₄ (18ml, 163.8mmol) was added dropwise. The solution was yellow and stirred for 5min; , N-diisopropylethylamine (30ml, 174mmol), dropwise, the reaction solution turned black, stirred for 1 hour; dropwise added compound IIa (44ml, 316.8mmol), dropwise, reacted at 0°C for 20 hours, and The liquid gradually turned yellow. Add 200ml of saturated NH ₄ Cl aqueous solution and 320ml of water, stir, separate the layers, extract the aqueous phase with ethyl acetate (70ml×2), combine the organic phases, wash with water and saturated brine in turn, and dry over anhydrous MgSO ₄ . Filtrate and concentrate under reduced pressure to obtain an oil, which was recrystallized from n-hexane and petroleum ether to obtain 44.1 g of a white solid with a yield of 75.4%. The structural identification data are the same as in Example 1.

Embodiment 3 The preparation of compound IVa

Under the protection of nitrogen, compound IIIa (40.0g, 153.2mmol) was dissolved in 500ml of anhydrous dimethyl sulfoxide, cooled to 0°C, and TiCl ₄ (18ml, 163.8mmol) was added dropwise. The solution turned yellow and stirred for 5min; Add dropwise N,N-diisopropylethylamine (30ml, 174mmol), dropwise, the reaction solution turns black, stir for 1 hour; dropwise add compound IIa (32ml, 229.8mmol), dropwise, react at 0°C for 20 After 1 hour, the reaction solution gradually turned yellow. Add 200ml of saturated NH ₄ Cl aqueous solution to quench the reaction, spin off the solvent under reduced pressure, add 320ml of water to the residue, extract with ethyl acetate (70ml×3), combine the organic phases, wash with water and saturated brine successively, anhydrous MgSO ₄ dry. Filtrate and concentrate under reduced pressure to obtain an oil, which was recrystallized from n-hexane and petroleum ether to obtain 36.6 g of a white solid with a yield of 62.6%. The structural identification data are the same as in Example 1.

Embodiment 4 The preparation of compound IVa

Under the protection of nitrogen, compound IIIa (40.0g, 153.2mmol) was dissolved in 500ml of anhydrous dioxane, cooled to 0°C, and TiCl ₄ (18ml, 163.8mmol) was added dropwise, the solution was yellow, and stirred for 1 hour ; Add dropwise N, N-diisopropylethylamine (30ml, 174mmol), dropwise, the reaction solution turns black, stir for 2.5 hours; dropwise add compound II a (64ml, 459.6mmol), dropwise, at 0°C After 20 hours of reaction, the reaction solution gradually turned yellow. Add 200ml of saturated NH ₄ Cl aqueous solution to quench the reaction, spin off the solvent under reduced pressure, add 320ml of water to the residue, extract with ethyl acetate (70ml×3), combine the organic phases, wash with water and saturated brine successively, anhydrous MgSO ₄ dry. Filtrate and concentrate under reduced pressure to obtain an oil, which was recrystallized from n-hexane and petroleum ether to obtain 37.6 g of a white solid with a yield of 64.3%. The structural identification data are the same as in Example 1.

Embodiment 5 The preparation of compound IVa

Under nitrogen protection, compound IIIa (40.0g, 153.2mmol) was dissolved in 500ml of anhydrous acetone, cooled to 0°C, and TiCl ₄ (18ml, 163.8mmol) was added dropwise. , N-diisopropylethylamine (30ml, 174mmol), dropwise, the reaction solution turned black, stirred for 4 hours; dropwise added compound II a (44ml, 316.8mmol), dropwise, reacted at 0 ° C for 20 hours, The reaction solution gradually turned yellow. Add 200ml of saturated NH ₄ Cl aqueous solution to quench the reaction, spin off the solvent under reduced pressure, add 320ml of water to the residue, extract with ethyl acetate (70ml×3), combine the organic phases, wash with water and saturated brine successively, anhydrous MgSO ₄ dry. Filtrate and concentrate under reduced pressure to obtain an oil, which was recrystallized from n-hexane and petroleum ether to obtain 37.3 g of a white solid with a yield of 63.8%. The structural identification data are the same as in Example 1.

Embodiment 6 The preparation of compound Va

Under nitrogen protection, compound IVa (46.7g, 122.3mmol) was dissolved in 500ml of a mixed solution of THF and H ₂ O with a volume ratio of 3:1, and when cooled to 0°C in an ice-salt bath, 30% H ₂ O ₂ aqueous solution (83.6ml, 819.4mmol), after dropping, LiOH·H ₂ O (10.3g, 244.6mmol) was added at the same temperature, slowly warmed to room temperature, and the reaction was complete in 6 hours. After cooling to below 0°C, an aqueous solution of Na ₂ SO ₃ (92.5 g, 733.8 mmol) was added dropwise, keeping the temperature of the system below 10°C during the dropwise addition. Filter, and wash the filter residue with cold water until the pH of the filtrate is about 12. The filtrate was evaporated to remove THF under reduced pressure at about 40°C, the remaining aqueous phase was washed with CH ₂ Cl ₂ (300ml×3), and the organic phase was discarded, and the pH of the aqueous phase was adjusted to about 2 with 4mol/L hydrochloric acid, and then used Extracted with CH ₂ Cl ₂ (300ml×3), combined the organic phases, washed with saturated brine, dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure to obtain 27.2g of oily substance with a yield of 96.3%.

Its structural identification data are as follows:

¹ H NMR (400MHz, CDCl ₃ ): δ7.25-7.4 (m, 5H); 4.54 (s, 2H); 3.73 (dd, J=9, 16Hz, 1H); 3.63 (dd, J=5, 9Hz , 1H); 3.68(m, 1H); 2.00(m, 1H); 0.99(d, J=7Hz, 3H); 0.96(d, J=7Hz, 3H).

Embodiment 7 The preparation of compound VIa

Under nitrogen protection, NaBH ₄ (7.0g, 183.8mmol) was suspended in 70ml of anhydrous THF, placed in an ice bath and cooled to below 10°C, a solution of compound Va (27.2g, 122.5mmol) in 230ml of THF was added dropwise, and stirred until no Bubbles were generated. After 5 minutes, BF ₃ ·Et ₂ O (19.4ml, 153.1mmol) was added dropwise at the same temperature. After the drop was completed, the mixture was stirred at room temperature and tracked by TLC. The reaction was complete in 3 hours. Cool to 0°C, slowly pour the reaction solution into 300ml of ice water, stir for 1h, extract with ethyl acetate (300ml×3), combine the organic phases, wash with saturated brine, and dry over anhydrous Na ₂ SO ₄ . After filtering and concentrating under reduced pressure, 23.6 g of oil was obtained, the yield was 92.6%, and the HPLC purity was above 97%.

Its structural identification data are as follows:

¹ H NMR (400MHz, CDCl ₃ ): δ7.25-7.4(m, 5H); 4.53(m, 2H); 3.55-3.8(m, 4H); 2.70(t, J=5Hz, 1H); 1.78( m, 1H); 1.65(m, 1H); 0.92(d, J=7Hz, 3H); 0.90(d, J=7Hz, 3H).

Experimental results under other reaction conditions: (except the reaction conditions in the table, all the other reaction conditions and operating process are the same as above)

serial number Reduction system Phase transfer catalyst Solvent Yield (%) 1 KBH ₄ +BF ₃ -Et ₂ O Tetra-n-butylammonium bromide ethylene glycol diethyl ether 80.2 2 KBH ₄ +KHSO ₄ Polyethylene glycol 400 ethylene glycol diethyl ether 75.4 3 KBH ₄ +DME·HCl none ethylene glycol diethyl ether 82.3 4 NaBH ₄ +BF ₃ -Et ₂ O none ethylene glycol diethyl ether 90.5 5 NaBH ₄ +KHSO ₄ Polyethylene glycol 400 ethylene glycol diethyl ether 85.4 6 NaBH ₄ +DME·HCl none ethylene glycol diethyl ether 87.8 7 KBH ₄ +BF ₃ -Et ₂ O none Anhydrous tetrahydrofuran 83.2 8 KBH ₄ +KHSO ₄ Polyethylene glycol 400 Anhydrous tetrahydrofuran 81.7 9 KBH ₄ +DME·HCl none Anhydrous tetrahydrofuran 79.5 10 NaBH ₄ +BF ₃ -Et ₂ O none Anhydrous tetrahydrofuran 92.6 11 NaBH ₄ +KHSO ₄ Polyethylene glycol 400 Anhydrous tetrahydrofuran 86.4 12 NaBH ₄ +DME·HCl none Anhydrous tetrahydrofuran 88.6

serial number Compound Va: NaBH ₄ : BF ₃ ·Et ₂ O (molar ratio) Solvent Yield (%) 1 1:1.35:1.0 Anhydrous tetrahydrofuran 80.4 2 1:1.5:1.0 Anhydrous tetrahydrofuran 84.8 3 1:1.7:1.0 Anhydrous tetrahydrofuran 83.2 4 1:1.9:1.0 Anhydrous tetrahydrofuran 82.5 5 1:2.0:1.0 Anhydrous tetrahydrofuran 82.8 6 1:2.2:1.0 Anhydrous tetrahydrofuran 80.1 7 1:2.5:1.0 Anhydrous tetrahydrofuran 79.2 8 1:1.35:1.1 Anhydrous tetrahydrofuran 86.5 9 1:1.5:1.1 Anhydrous tetrahydrofuran 85.5 10 1:1.5:1.2 Anhydrous tetrahydrofuran 92.0 11 1:1.5:1.3 Anhydrous tetrahydrofuran 91.3 12 1:1.5:1.4 Anhydrous tetrahydrofuran 90.2 13 1:1.5:1.5 Anhydrous tetrahydrofuran 89.6

14 1:1.7:1.1 Anhydrous tetrahydrofuran 86.7 15 1:1.7:1.2 Anhydrous tetrahydrofuran 87.9 16 1:1.7:1.3 Anhydrous tetrahydrofuran 90.8 17 1:1.7:1.5 Anhydrous tetrahydrofuran 89.6

Example 8 Preparation of Compound Ia

Under the protection of nitrogen, the compound VIa (22.7g, 109.1mmol) was dissolved in 200ml ethyl acetate, cooled to about 5°C in an ice bath, and PBr ₃ (4.5ml, 47mmol) was added dropwise. . After 1 hour, the temperature was raised to 50°C for reaction, followed by TLC, and the reaction was complete in 5 hours. Cool to below 10°C, add 200ml of water to quench, separate the layers, extract the aqueous phase with ethyl acetate (200ml×2), combine the organic phases, wash with saturated sodium bicarbonate solution and saturated brine successively, and anhydrous Na ₂ SO ₄ was dried, filtered, and concentrated under reduced pressure to obtain 22.5 g of light yellow oil, with a yield of 75.9% and an HPLC purity of over 98.3%.

Its structural identification data are as follows:

¹ H NMR (400MHz, CDCl ₃ ): δ7.25-7.4(m, 5H); 4.53(s, 2H); 3.43-3.75(m, 4H); 1.84(m, 1H); 1.71(m, 1H) ; 0.96 (d, J = 7Hz, 3H); 0.92 (d, J = 7Hz, 3H).

serial number Compound VIa:PBr ₃ (molar ratio) The temperature at the time of dropping Solvent Yield (%) 1 1:0.4 0℃ Dichloromethane 60.5 2 1:0.45 0℃ dichloromethane 62.8 3 1:0.5 0℃ Dichloromethane 68.6 4 1:0.6 0℃ dichloromethane 67.5 5 1:0.7 0℃ Dichloromethane 69.3 6 1:0.8 0℃ Dichloromethane 68.5 7 1:0.4 0℃ Ethyl acetate 72.3 8 1:0.45 0℃ Ethyl acetate 75.4 9 1:0.5 0℃ Ethyl acetate 75.8

10 1:0.6 0℃ Ethyl acetate 74.6 11 1:0.7 0℃ Ethyl acetate 74.2 12 1:0.8 0℃ Ethyl acetate 72.1 13 1:0.45 -20℃ Ethyl acetate 69.2 14 1:0.45 -10℃ Ethyl acetate 71.8 15 1:0.45 -5°C Ethyl acetate 73.6 16 1:0.45 0℃ Ethyl acetate 74.5

Claims (5)

1. a preparation method of oxazolidinone derivatives as shown in formula IV, it is characterized in that comprising the following steps: Under the protection of nitrogen, dissolve 40.0g of compound III in 500ml of anhydrous CH ₂ Cl ₂ , cool to 0°C, add 163.8mmol of TiCl ₄ dropwise, and stir for 5min; add 174mmol of N,N-diisopropylethylamine dropwise After dropping, stir for 1 hour; add 316.8mmol of compound II dropwise, react at 0°C for 20 hours, add 200ml of saturated NH ₄ Cl aqueous solution and 320ml of water, stir, separate liquids, and use CH ₂ Cl ₂ 70ml× 2 extraction, the organic phases were combined, washed with water and saturated brine successively, dried over anhydrous MgSO ₄ , filtered, and concentrated under reduced pressure to obtain an oil, which was recrystallized with n-hexane and petroleum ether to obtain a white solid. 2. A preparation method of oxazolidinone derivatives as shown in formula IV, characterized in that: Under the protection of nitrogen, dissolve 40.0g of compound III in 500ml of anhydrous CH ₂ Cl ₂ , cool to 0°C, add TiCl ₄ dropwise, and stir for 5min; add N,N-diisopropylethylamine dropwise, and dropwise , stirred for 1 hour; added compound II 316.8mmol dropwise, and reacted at 0°C for 20 hours, added 200ml saturated NH ₄ Cl aqueous solution and 320ml water, stirred, separated, and extracted the aqueous phase with CH ₂ Cl ₂ 70ml×2, The organic phases were combined, washed with water and saturated brine successively, dried over anhydrous MgSO ₄ , filtered, and concentrated under reduced pressure to obtain an oil, which was recrystallized with n-hexane and petroleum ether to obtain a white solid; among them, compound III, N,N- The molar ratio of diisopropylethylamine and _TiCl4 is 1:1.0:1.0, 1:1.1:1.0, 1:1.2:1.0, 1:1.2:1.1, 1:1.3:1.1, 1:1.5:1.2, 1 :2.0:1.1, 1:3.0:1.1, 1:5.0:1.1, 1:1.2:1.2, 1:1.2:1.35, 1:1.2:1.5, or 1:1.2:2.0. 3. A preparation method of an oxazolidinone derivative as shown in formula IV, characterized in that it comprises the following steps: Under the protection of nitrogen, dissolve 40.0 g of compound III in 500 ml of anhydrous CH ₂ Cl ₂ , cool, add TiCl ₄ dropwise, and stir for 5 min; add N,N-diisopropylethylamine dropwise, and stir for 1 Hours; add compound II 316.8mmol dropwise, dropwise, react for 20 hours, add 200ml saturated NH ₄ Cl aqueous solution and 320ml water, stir, separate liquids, extract the aqueous phase with CH ₂ Cl ₂ 70ml×2, combine the organic phases, and successively use water Wash with saturated brine, dry over anhydrous MgSO ₄ , filter, and concentrate under reduced pressure to obtain an oil, which is recrystallized with n-hexane and petroleum ether to obtain a white solid; wherein, compound III, N,N-diisopropylethylamine The molar ratio with TiCl ₄ is 1:1.2:1.1; the cooling temperature is the same as the reaction temperature, which is -5°C, -10°C, -20°C or 10°C. 4. A method for preparing an oxazolidinone derivative as shown in formula IV, characterized in that it comprises the following steps: Under the protection of nitrogen, dissolve 40.0 g of compound III in 500 ml of anhydrous tetrahydrofuran, add 163.8 mmol of TiCl ₄ dropwise at 0°C, and stir for 5 minutes; add 174 mmol of N,N-diisopropylethylamine dropwise, and stir after dropping 1 hour; add compound II 316.8mmol dropwise, react at 0°C for 20 hours, add 200ml saturated NH ₄ Cl aqueous solution and 320ml water, stir, separate liquids, extract the aqueous phase with ethyl acetate 70ml×2, combine the organic phases , washed with water and saturated brine successively, dried over anhydrous MgSO ₄ , filtered, and concentrated under reduced pressure to obtain an oil, which was recrystallized with n-hexane and petroleum ether to obtain a white solid. 5. A method for preparing an oxazolidinone derivative as shown in formula IV, characterized in that it comprises the following steps: Under the protection of nitrogen, dissolve 40.0 g of compound III in 500 ml of anhydrous tetrahydrofuran, add TiCl ₄ dropwise at 0°C, and stir for 5 minutes; add N,N-diisopropylethylamine dropwise, and stir for 1 hour; Add compound II 316.8mmol dropwise, and react at 0°C for 20 hours, add 200ml saturated NH ₄ Cl aqueous solution and 320ml water, stir, separate liquids, extract the aqueous phase with CH ₂ Cl ₂ 70ml×2, combine the organic phases, and then Wash with water and saturated brine, dry over anhydrous MgSO ₄ , filter, and concentrate under reduced pressure to obtain an oil, which is recrystallized with n-hexane and petroleum ether to obtain a white solid; wherein, compound III, N,N-diisopropylethyl The molar ratio of amine to _TiCl4 is 1:1.2:1.1.