A racemization recovery method for the by-product of the resolution of a letermovir intermediate

Abstract

The invention discloses a racemization recovery method for a by-product of the splitting of a letermovir intermediate, which comprises the following steps: 1) the mother liquor after the splitting of letermovir methyl ester I by D-DTTA is concentrated under reduced pressure, and then L-DTTA is added to form a salt to precipitate to obtain the letermovir methyl ester L-DTTA salt shown in formula III; 2) the letermovir methyl ester L-DTTA salt is freed to obtain compound IV; 3) the temperature is controlled at 12-50°C, a solution of compound IV is slowly dripped into a suspension of potassium tert-butoxide, and the reaction is carried out by heat preservation to obtain the intermediate shown in formula V; after determining that all the raw materials have reacted, water is added without separation, the temperature is raised to 50°C-reflux temperature for reaction, and after the reaction is completed, compound VI is separated to obtain compound VI; 4) compound VI is subjected to esterification reaction to obtain letermovir methyl ester I. The invention has the advantages of mild reaction conditions, simple operation, short reaction time, significantly reduced energy consumption, high product yield and good quality, etc.

Description

Technical Field

[0001] The invention belongs to the field of drug synthesis, and more specifically, relates to a racemization recovery method for a by-product of the resolution of a Letermovir intermediate. Background Art

[0002] Letermovir (LMV) is a potent anti-cytomegalovirus drug. It was originally developed by AiCuris anti-infective cures GmbH in Germany and acquired by Merck & Co, a subsidiary of Merck, on October 15, 2012, which is responsible for clinical trials, marketing approval, production and sales. Clinical studies have shown that Letermovir has good safety and efficacy. After 28 days of treatment, cytomegalovirus was not detected in the patient's body. Compared with other approved drugs, there is no cross-resistance and it has good market prospects. The chemical structure is shown below:

[0003]

[0004] Patent WO2006133822A provides the following preparation method: 2-halogen-substituted aniline is directly reacted with isocyanate, and then reacted with alkyl acrylate to obtain {8-fluoro-3-[2-methoxy-5-(trifluoromethyl)phenyl]-2-oxo-1,2,3,4-tetrahydroquinazolin-4-yl}acetic acid methyl ester. After that, it is chlorinated with phosphorus oxychloride, and then reacted with 3-methoxyphenylpiperazine to obtain {8-fluoro-2-[4-(3-methoxyphenyl)piperazine-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydroquinazolin-4-yl} methyl acetate, which is then split by D-DTTA (D-di-p-methylbenzoyltartaric acid) to obtain chiral {8-fluoro-2-[4-(3-methoxyphenyl)piperazine-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydroquinazolin-4-yl} methyl acetate, which is then hydrolyzed to obtain the product LMV. The price of the raw materials of this route is relatively high. The chiral intermediate is split twice by the chiral acid splitting method, and the splitting yield is about 30%.

[0005]

[0006] Chiral splitting has the disadvantages of low raw material utilization and low yield, which is one of the reasons for the high cost of Letermovir API. The method of racemizing the mother liquor after chiral splitting, then recovering the Letermovir intermediate and splitting it again is an effective means to improve the utilization of raw materials and reduce costs.

[0007] Patent WO2006133822A also reports a racemization recovery process for LMV intermediate mother liquor. First, L-DTTA (L-di-p-methylbenzoyltartaric acid) is added to the racemization mother liquor to obtain (R)-{8-fluoro-2-[4-(3-methoxyphenyl)piperazine-1-yl]-3-(2-methoxy-5-trifluoromethylphenyl)-3,4-dihydroquinazolin-4-yl}acetic acid methyl ester salt (Compound III); secondly, it is freed, then dissolved in acetonitrile, and racemized with sodium methoxide solution to obtain Compound VI; thirdly, it is methylated with sulfuric acid and methanol to obtain Compound I, and then split again to obtain the target Compound II. However, the racemization rate of this process is only (R:S=54:46), the reaction time reaches 36-72h, and the yield is only 25.7%, which is far lower than the theoretical yield (theoretical yield is 50%).

[0008] Therefore, a racemization recovery method for the by-products of the splitting of Letermovir was explored to achieve the purpose of reducing the production cost of Letermovir raw materials, thereby reducing the price of Letermovir-related preparations, which is of great significance to reducing the cost of medication for patients. Summary of the invention

[0009] Based on the above-mentioned shortcomings of the prior art, the present invention proposes a racemization recovery method for the splitting by-products of the Letermovir intermediate, which solves the problem of high production costs of Letermovir APIs and preparations.

[0010] The technical solution adopted by the present invention is described in detail below.

[0011] A racemization recovery method for a byproduct of the resolution of a Letermovir intermediate comprises the following steps:

[0012] 1) In the production process of letermovir, the mother liquor after the letermovir methyl ester shown in formula I is split by D-DTTA is concentrated under reduced pressure, and then L-DTTA is added to form a salt to obtain the letermovir methyl ester·L-DTTA salt shown in formula III;

[0013] 2) suspending Temovir methyl ester·L-DTTA salt in methyl tert-butyl ether (MTBE) solvent, adding saturated sodium bicarbonate solution, stirring until the two phases are clear, separating the liquids, and concentrating the organic layer to obtain an oily substance, namely compound IV;

[0014] 3) dispersing compound IV and potassium tert-butoxide with organic solvent A respectively to obtain a solution of compound IV and a suspension of potassium tert-butoxide, then controlling the temperature at 12-50° C., slowly dripping the solution of compound IV into the suspension of potassium tert-butoxide, and keeping the temperature to react to obtain an intermediate represented by formula V; after ensuring that all the raw materials have reacted, adding an appropriate amount of water without separation, raising the temperature to a temperature between 50° C. and reflux temperature to react, and separating to obtain compound VI after the reaction is completed; the organic solvent A is selected from one or more of dioxane, tetrahydrofuran, 2-methyltetrahydrofuran and ethylene glycol dimethyl ether;

[0015] 4) Under the action of concentrated sulfuric acid, compound VI and methanol are subjected to an esterification reaction to obtain letermovir methyl ester as shown in formula I;

[0016] The specific reaction is as follows:

[0017]

[0018] The mother liquor after the D-DTTA splitting of the letermovir methyl ester shown in formula I in the letermovir production process described in step 1) of the present invention can be obtained by referring to the operation of the embodiment of patent CN101213180B, that is, the {8-fluoro-2-[4-(3-methoxyphenyl)piperazine-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydroquinazolin-4-yl}acetic acid methyl ester shown in formula I is split using D-DTTA, and the reaction liquid after splitting is filtered, and the filter cake is (2S,3S)-2,3-bis[(4-methylbenzoyl)oxy]succinic acid-{8-fluoro-2-[4-(3-methoxyphenyl)piperazine-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydroquinazolin-4-yl}acetic acid methyl ester (1:1 salt) shown in formula II, and the filtrate is the mother liquor after splitting.

[0019] Step 1) of the present invention can refer to the operation of Example 12 in CN101213180B to crystallize the R configuration, i.e., letermovir methyl ester·L-DTTA salt shown in Formula III, from the mother liquor after separation. In short, the mother liquor is washed with a saturated sodium bicarbonate aqueous solution, the organic phase is dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a residue; the residue is dissolved in ethyl acetate, and recrystallized with L-DTTA, and the crystals are dried to obtain letermovir methyl ester·L-DTTA salt as shown in Formula III, whose chemical name is (2R, 3R)-2,3-bis[(4-methylbenzoyl)oxy]succinic acid-{8-fluoro-2-[4-(3-methoxyphenyl)piperazine-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydroquinazolin-4-yl}acetic acid methyl ester (1:1 salt).

[0020] In step 2) of the present invention, the mass volume ratio of letermovir methyl ester·L-DTTA salt:MTBE:saturated sodium bicarbonate is preferably 1 g:(5-10) mL:(5-10) mL.

[0021] In step 3) of the present invention, the organic solvent A is preferably dioxane.

[0022] In step 3) of the present invention, the mass ratio of letermovir methyl ester·L-DTTA salt: organic solvent A: potassium tert-butoxide is preferably 1:3-8:0.2-1.

[0023] In step 3) of the present invention, the temperature is preferably controlled at 12-18° C., and the solution of compound IV is slowly dripped into the suspension of potassium tert-butoxide. After the dripping is completed, the reaction is kept warm until all the raw materials react (the reaction time is generally about 1 hour) to obtain the intermediate shown in formula V. Carrying out the reaction within this temperature range is conducive to reducing the impurity content.

[0024] In step 3) of the present invention, the separation is preferably carried out by the following steps: after the reaction is completed, the mixture is concentrated under reduced pressure in a water bath at 50-60° C. until small vacuoles gradually disappear or it is difficult to evaporate the liquid; after the distillation is completed, water and dichloromethane are added, the pH is adjusted to 5-6 with hydrochloric acid, the liquids are separated, the water layer is extracted with dichloromethane again, the organic phases are combined, the organic phases are dried over anhydrous sodium sulfate and rotary concentrated to obtain a hard foam compound VI.

[0025] In step 3) of the present invention, water is preferably added to the reaction system, and the temperature is raised to 50-60° C. and the reaction is maintained for 1-3 h (optimally 2 h).

[0026] In step 3) of the present invention, the mass of water added to the reaction system is preferably 0.2-3 times the mass of letermovir methyl ester·L-DTTA salt required for preparing the compound IV.

[0027] Step 4) of the present invention is specifically implemented as follows: concentrated sulfuric acid is slowly added to a methanol solution of compound VI, the temperature is raised to reflux temperature under a nitrogen atmosphere for reaction for 3-4 hours, and compound I is obtained by post-treatment. The post-treatment step is: the reaction mixture is cooled to below 45°C and distilled under reduced pressure, the external temperature is maintained at 40-50°C, most of the solvent is distilled off, water and DCM are then added, the organic phase is then separated, the organic phase is extracted with a saturated sodium bicarbonate solution, the organic phase is dried over anhydrous sodium sulfate, and concentrated to obtain compound I.

[0028] Compared with the prior art, the present invention has the following beneficial effects:

[0029] 1) The present invention creatively proposes a new racemization method, in which compound III is reacted with potassium tert-butoxide in a specific organic solvent A system to extract hydrogen to generate a new stable intermediate V, which significantly shortens the overall reaction time and improves the racemization rate and yield;

[0030] 2) In the reaction process of the present invention, the solution of formula IV is dripped into the suspension of potassium tert-butoxide, which can well control the reaction speed to proceed smoothly without abnormal conditions of unstable temperature and pressure, thereby ensuring safe and stable production, thereby reducing the generation of impurities and indirectly improving the quality of the product.

[0031] 3) The racemic product obtained by the present invention can reach R / S=1:1 at the highest, and the racemic product can be repeatedly split into salts to prepare the final chiral product.

[0032] 4) In summary, the present invention has the advantages of mild reaction conditions, simple operation, short reaction time, significantly reduced energy consumption, high product yield and high quality, etc., has obvious economic and social benefits, is suitable for industrial production, and is a method for racemization of a letermovir intermediate with good application prospects.

[0033] 5) The present invention provides a new compound V. The compound is generated in the racemization recovery process of the byproduct of the resolution of the intermediate of Letermovir, and is used as an intermediate compound, and then hydrolyzed to obtain the target product. Compared with the previous report, this process significantly shortens the reaction time and improves the racemization rate. BRIEF DESCRIPTION OF THE DRAWINGS

[0034] Figure 1 This is the HPLC spectrum of compound VI prepared in Example 2.

[0035] Figure 2 This is the chiral HPLC spectrum of compound VI prepared in Example 2.

[0036] Figure 3 This is the HPLC spectrum of Compound I prepared in Example 5. DETAILED DESCRIPTION

[0037] In order to make the purpose, technical solutions and advantages of the present invention more clearly understood, the present invention is described with the following specific embodiments, but the present invention is by no means limited to these embodiments. The following are only preferred embodiments of the present invention, which are only used to explain the present invention and cannot be understood as limiting the scope of the patent of the present invention. It should be pointed out that any modification, equivalent substitution and improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

[0038] Part 1: Recovery of (R)-{8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydroquinazolin-4-yl}acetic acid methyl ester salt from mother liquor after chemical resolution

[0039] Example 1: Crystallization of R configuration from split mother liquor

[0040] The mother liquor (300 g) of the crystallization of (2S,3S)-2,3-bis[(4-methylbenzoyl)oxy]succinic acid-{8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydroquinazolin-4-yl}acetic acid methyl ester (1:1 salt) was shaken with saturated aqueous sodium bicarbonate solution (1.5 L), the phases were separated, and the organic phase was dried over anhydrous sodium sulfate and concentrated on a rotary evaporator. The residue (210 g) was dissolved in ethyl acetate (1.6 L), followed by the addition of (2R,3R)-2,3-bis[(4-methylbenzoyl)oxy]succinic acid (122 g) and the mixture was stirred at room temperature for 10 minutes, solid precipitated, then cooled to 0-3° C. and stirred for another 3 h. The suspension was collected by suction filtration and washed with cold ethyl acetate (0-10°C, 500 mL). The crystalline form was dried in VDO at 40°C for 18 h using inhaled nitrogen. A total of 160 g of the salt of formula III was obtained, with an HPLC purity of 98.5%, chiral HPLC: R-type purity of 98.6%, and purity of S-type of 1.4%. The salt of formula III prepared in this example was used in the following examples and comparative examples.

[0041] Part II Racemization

[0042] Example 2

[0043] 1) Free: At room temperature, weigh 30g of the salt represented by formula III and add it to a 1L flask, pour in 210mL MTBE, then slowly add 150mL saturated sodium bicarbonate solution and stir for 30min until the two phases are clear. Then separate the liquids, take the organic layer and concentrate it to obtain an oily substance represented by formula IV;

[0044] 2) Racemization: Add 15g potassium tert-butoxide and 100g dioxane to a dry, clean 500mL three-necked flask in sequence; dissolve the oily substance of Formula IV in 1) with 50g dioxane, shake thoroughly and place in a constant pressure dropping funnel, then slowly drip into the three-necked flask, control the temperature at 12-18°C, and keep warm for 1h after the addition is completed to obtain Formula V. After the sampling point plate confirms that all the raw materials have reacted, add 21g water to the flask, heat to 50-60°C and keep warm for 2h. After the reaction is completed, concentrate under reduced pressure in a water bath at 50°C until small bubbles gradually disappear or it is difficult to evaporate the liquid. After the distillation, water (83 g) and DCM (108 g) were added, pH=6 was adjusted with 1N hydrochloric acid, the liquid was separated, the aqueous layer was extracted with DCM (108 g) again, the organic phases were combined, the organic phases were dried over anhydrous sodium sulfate and rotary concentrated to obtain hard foam VI (16.2 g, HPLC purity 98.6%). The chiral HPLC results of the product VI: R type purity 50.1%, S type purity 49.9%.

[0045] Characterization of the compound of formula VI:

[0046] 1 H NMR(400MHz, CDCl3) δ7.56(dd,J=8.8,2.7Hz,1H),7.41(brs,1H),7.25(d,J=8.3Hz,1H),7.09( t,J=8.1Hz,1H),7.12–7.01(m,1H),6.94–6.83(m,2H),6.47(dd,J=8.1,2.6Hz,1H),6.41(t,J= 2.3Hz,1H),6.38(dd,J=7.8,2.4Hz,1H),4.89(t,J=7.3Hz,1H),3.81(brs,3H),3.70(s,3H),3. 53-3.40(m,4H),2.98-2.83(m,4H),2.79(dd,J=14.7,7.5Hz,1H),2.45(dd,J=14.7,7.3Hz,1H).

[0047] 13 C NMR (101MHz, CDCl3) δ171.86,160.15,156.57,154.55(d,J CF =246.1Hz),153.18,152.22,134.19,132.3(d,J CF =11.6Hz),129.65,124.08(q,J CF =272.7Hz),123.86(q,J CF =3.9Hz),122.40,122.07(q,JCF =7.3Hz),121.4(q,J CF =30.0Hz),123.87,114.5(d,J CF =19.0Hz),113.36,108.31,104.67,101.90,59.01,56.35,54.89,47.92,45.58,40.0.

[0048] High resolution mass spectrum (ESI-HRMS): m / z = 573.2125 [M+H] + , theory: 573.2119.

[0049] HPLC spectrum see Figure 1 and Figure 2 ,Depend on Figure 1 It can be seen that the HPLC purity of compound VI is 98.6%; Figure 2 It can be seen that the purity of R type is 50.1% and the purity of S type is 49.9%.

[0050] Example 3

[0051] 1) Free: At room temperature, weigh 30g of the salt of formula III and add it to a 1L flask, pour in 210mL MTBE, then slowly add 150mL saturated sodium bicarbonate solution, stir for 30min until the two phases are clear. Then separate the liquids, take the organic layer, and concentrate to obtain an oily substance of formula IV;

[0052] 2) Racemization: Add 30g potassium tert-butoxide and 80g dioxane to a dry, clean 500mL three-necked flask in sequence; dissolve the oily substance of Formula IV in 1) with 40g dioxane, shake thoroughly and place in a constant pressure dropping funnel, then slowly drip into the three-necked flask, control the temperature at 30-40°C, and keep warm for 1h after the addition is completed to obtain Formula V. After the sampling point plate confirms that all the raw materials have reacted, add 45g water to the flask, heat to 50-60°C and keep warm for 1h. After the reaction is completed, concentrate under reduced pressure in a water bath at 50°C until small bubbles gradually disappear or it is difficult to evaporate the liquid. After the distillation, water (83 g) and DCM (108 g) were added, pH=6 was adjusted with 1N hydrochloric acid, the liquid was separated, the aqueous layer was extracted with DCM (108 g) again, the organic phases were combined, the organic phases were dried over anhydrous sodium sulfate and rotary concentrated to obtain hard foam VI (16.1 g, HPLC purity 96.8%). Chiral HPLC of product VI: R type purity 50.2%, S type purity 49.8%.

[0053] Example 4

[0054] 1) Free: At room temperature, weigh 30g of the salt of formula III and add it to a 1L flask, then pour in 210g of MTBE, then slowly add 150g of saturated sodium bicarbonate solution, and stir for 30min until the two phases are clear. Then separate the liquids, take the organic layer, and concentrate it to obtain an oily substance of formula IV;

[0055] 2) Racemization: Add 9g potassium tert-butoxide and 80g dioxane to a dry, clean 500mL three-necked flask in sequence; dissolve the oily substance of Formula IV in 1) with 40g dioxane, shake thoroughly and place in a constant pressure dropping funnel, then slowly drip into the three-necked flask, control the temperature at 15-25°C, and keep warm for 1h after the addition is completed to obtain Formula V. After the sampling point plate confirms that all the raw materials have reacted, add 45g water to the flask, heat to 50-60°C and keep warm for 2h. After the reaction is completed, concentrate under reduced pressure in a water bath at 50°C until small bubbles gradually disappear or it is difficult to evaporate the liquid. After the distillation, water (83 g) and DCM (108 g) were added, pH=6 was adjusted with 1N hydrochloric acid, the liquid was separated, the aqueous layer was extracted with DCM (108 g) again, the organic phases were combined, the organic phases were dried over anhydrous sodium sulfate and rotary concentrated to obtain hard foam VI (15.8 g, HPLC purity 97.3%). Chiral HPLC of product VI: R type purity 50.1%, S type purity 49.9%.

[0056] Example 5

[0057] 1) Free: At room temperature, weigh 30g of the salt of formula III and add it to a 1L flask, then pour in 210g of MTBE, then slowly add 150g of saturated sodium bicarbonate solution, and stir for 30min until the two phases are clear. Then separate the liquids, take the organic layer, and concentrate it to obtain an oily substance of formula IV;

[0058] 2) Racemization: Add 24g potassium tert-butoxide and 140g dioxane to a dry, clean 500mL three-necked flask in sequence; dissolve the oily substance of Formula IV in 1) with 70g dioxane, shake thoroughly and place in a constant pressure dropping funnel, then slowly drip into the three-necked flask, control the temperature at 40-50°C, and keep warm for 1h after the addition is completed to obtain Formula V. After the sampling point plate confirms that all the raw materials have reacted, add 60g water to the flask, heat to 50-60°C and keep warm for 2h. After the reaction is completed, concentrate under reduced pressure in a water bath at 50°C until small bubbles gradually disappear or it is difficult to evaporate the liquid. After the distillation, water (83 g) and DCM (108 g) were added, pH=6 was adjusted with 1N hydrochloric acid, the liquid was separated, the aqueous layer was extracted with DCM (108 g) again, the organic phases were combined, the organic phases were dried over anhydrous sodium sulfate and rotary concentrated to obtain hard foam VI (16.2 g, HPLC purity 96.6%). Chiral HPLC of product VI: R type purity 50.1%, S type purity 49.9%.

[0059] Example 6

[0060] 1) Free: At room temperature, weigh 30g of the salt represented by formula III and add it to a 1L flask, pour in 210mL MTBE, then slowly add 150mL saturated sodium bicarbonate solution and stir for 30min until the two phases are clear. Then separate the liquids, take the organic layer and concentrate it to obtain an oily substance represented by formula IV;

[0061] 2) Racemization: Add 15g potassium tert-butoxide and 100g tetrahydrofuran to a dry, clean 500mL three-necked flask in sequence; dissolve the oily substance of Formula IV in 1) in 50g tetrahydrofuran, shake it thoroughly and place it in a constant pressure dropping funnel, then slowly drip it into the three-necked flask, control the temperature at 12-18°C, and keep it warm for 1h after the addition is completed to obtain Formula V. After the sampling point plate confirms that all the raw materials have reacted, add 21g water to the flask, heat it to 50-60°C and keep it warm for 2h. After the reaction is completed, concentrate it in a water bath at 50°C under reduced pressure until the small bubbles gradually disappear or it is difficult to evaporate the liquid. After the distillation, water (83 g) and DCM (108 g) were added, pH=6 was adjusted with 1N hydrochloric acid, the liquid was separated, the aqueous layer was extracted with DCM (108 g) again, the organic phases were combined, the organic phases were dried over anhydrous sodium sulfate and rotary concentrated to obtain hard foam VI (15.9 g, HPLC purity 97.8%). The chiral HPLC results of the product VI: R type purity 50.3%, S type purity 49.7%.

[0062] Example 7

[0063] 1) Free: At room temperature, weigh 30g of the salt represented by formula III and add it to a 1L flask, pour in 210mL of MTBE solution, then slowly add 150mL of saturated sodium bicarbonate solution and stir for 30min until the two phases are clear. Then separate the liquids, take the organic layer and concentrate it to obtain an oily substance represented by formula IV;

[0064] 2) Racemization: Put 15g potassium tert-butoxide and 100g 2-methyltetrahydrofuran into a dry, clean 500mL three-necked flask in turn; dissolve the oily substance of Formula IV in 1) with 50g 2-methyltetrahydrofuran, shake it thoroughly and place it in a constant pressure dropping funnel, then slowly drip it into the three-necked flask, control the temperature at 12-18°C, and keep it warm for 1h after the addition is completed to obtain Formula V. After the sampling point plate confirms that all the raw materials have reacted, add 21g water to the flask, heat it to 50-60°C and keep it warm for 2h. After the reaction is completed, concentrate it under reduced pressure in a water bath at 50°C until the small bubbles gradually disappear or it is difficult to evaporate the liquid. After the distillation, water (83 g) and DCM (108 g) were added, pH=6 was adjusted with 1N hydrochloric acid, the liquid was separated, the aqueous layer was extracted with DCM (108 g) again, the organic phases were combined, the organic phases were dried over anhydrous sodium sulfate and rotary concentrated to obtain hard foam VI (15.7 g, HPLC purity 97.6%). The chiral HPLC results of the product VI: R type purity 50.4%, S type purity 49.6%.

[0065] Example 8

[0066] 1) Free: At room temperature, weigh 30g of the salt represented by formula III and add it to a 1L flask, pour in 210mL MTBE, then slowly add 150mL saturated sodium bicarbonate solution, stir for 3h until the two phases are clear. Then separate the liquids, take the organic layer, and concentrate to obtain an oil represented by formula IV;

[0067] 2) Racemization: Add 15g potassium tert-butoxide and 100g ethylene glycol dimethyl ether to a dry, clean 500mL three-necked flask in sequence; dissolve the oily substance of Formula IV in 1) with 50g ethylene glycol dimethyl ether, shake it thoroughly and place it in a constant pressure dropping funnel, then slowly drip it into the three-necked flask, control the temperature at 12-18°C, and keep it warm for 1h after the addition is completed to obtain Formula V. After the sampling point plate confirms that all the raw materials have reacted, add 21g water to the flask, heat it to 50-60°C and keep it warm for 2h. After the reaction is completed, concentrate it in a water bath at 50°C under reduced pressure until the small bubbles gradually disappear, or it is difficult to evaporate the liquid. After the distillation, water (83 g) and DCM (108 g) were added, pH=6 was adjusted with 1N hydrochloric acid, the liquid was separated, the aqueous layer was extracted with DCM (108 g) again, the organic phases were combined, the organic phases were dried over anhydrous sodium sulfate and rotary concentrated to obtain hard foam VI (16.1 g, HPLC purity 98.4%). Chiral HPLC of product VI: R type purity 50.4%, S type purity 49.6%.

[0068] Example 9: Characterization of Compound V

[0069] 1) Free: At room temperature, weigh 30g of the salt represented by formula III and add it to a 1L flask, pour in 210mL of MTBE solution, then slowly add 150mL of saturated sodium bicarbonate solution and stir for 3h until the two phases are clear. Then separate the liquids, take the organic layer and concentrate it to obtain an oily substance represented by formula IV;

[0070] 2) Racemization: Add 15g potassium tert-butoxide and 100g dioxane to a dry, clean 500mL three-necked flask, stir and cool to 12-18°C; dissolve the oily substance of Formula IV in 1) with 50g dioxane solution, shake thoroughly and place in a constant pressure dropping funnel, then slowly drip into the three-necked flask, control the temperature at 12-18°C, keep warm for 1h after the addition, and take a sampling point plate to determine that all the raw materials have reacted. Add water (83g) and DCM (108g), adjust pH to 7 with 1N hydrochloric acid, separate the liquids, extract the water layer with DCM (108g) again, combine the organic phases, dry the organic phases over anhydrous sodium sulfate and rotary concentrate to obtain Formula V (15g).

[0071] The hydrogen spectrum, carbon spectrum and high-resolution mass spectrum information of compound V are as follows:

[0072] 1 H NMR(400MHz, CDCl3)δ7.43(d,J=9.5Hz,1H),7.18(dd,J=16.0,8.1Hz,2H),7.09(m,2H),6.95(d,J=8.3Hz,1H), 6.87(m,1H),6.58(d,J=8.1Hz,1H),6.55–6.40(m,4H),4.14(d,J=31.2Hz,2H),3.80(s,3H),3.69–2.97(m,9H).

[0073] 13C NMR (101MHz, CDCl3) δ160.64(s), 160.44(s), 153.93(s), 152.51(s), 151.04-148.56(d, J=250.5Hz), 145.36(s), 139.92(d,J=2.5Hz),137.59(s),129.92(s),126.42(d,J=8.3Hz),125.54(s),123.99(d,J=3.5Hz),123.37(d,J= 7.8Hz),122.84(s),122.70–121.73(q,J=97.9Hz),122.2(d,J=1.0Hz),122.15(s),120.51(q,J=4.2Hz),119.70( q,J=3.5Hz),116.92(d,J=21.0Hz),109.53-109.35(d),105.04(s),103.05(s),55.24(s),48.85(br),44.96(br).

[0074] High resolution mass spectrum (ESI-HRMS): m / z = 555.2069 [M+H] + , theory: 555.2014

[0075] Comparative Example 1

[0076] 1) Free: At room temperature, weigh 30g of the salt of formula III and add it to a 1L flask, then pour in 210g of MTBE, then slowly add 150g of saturated sodium bicarbonate solution, and stir for 30min until the two phases are clear. Then separate the liquids, take the organic layer, and concentrate it to obtain an oily substance of formula IV;

[0077] 2) Racemization: Put 210g of dioxane in a dry, clean 500mL three-necked flask to dissolve the oily substance of Formula IV in 1, add 60g of water and 24g of potassium tert-butoxide, stir and heat to reflux for 1h. After the reaction is completed, concentrate under reduced pressure in a water bath at 50°C until the small vacuoles gradually disappear or it is difficult to evaporate the liquid. After the distillation is completed, add water (83g) and DCM (108g), adjust pH to 6 with 1N hydrochloric acid, separate the liquids, extract the water layer with DCM (108g) again, combine the organic phases, dry the organic phases over anhydrous sodium sulfate and rotary concentrate to obtain hard foam Formula VI (16.1g, HPLC purity 98.3%). Chiral HPLC: R type purity 97.1%, S type purity 2.9%.

[0078] Comparative Example 2

[0079] 1) Free: At room temperature, weigh 30g of the salt of formula III and add it to a 1L flask, then pour in 210g of MTBE, then slowly add 150g of saturated sodium bicarbonate solution, and stir for 30min until the two phases are clear. Then separate the liquids, take the organic layer, and concentrate it to obtain an oily substance of formula IV;

[0080] 2) Racemization: 270g tert-butanol dissolve the oily substance of Formula IV in 1) and 24g potassium tert-butoxide are added to a dry, clean 500mL three-necked flask in turn, stirred at room temperature for 1h, then 60g water is added (if water is not added here, the reaction time will be greatly extended), and the temperature is raised to reflux for 1h. After the reaction is completed, the mixture is concentrated under reduced pressure in a water bath at 50°C until the small vacuoles gradually disappear or it is difficult to evaporate the liquid. After the distillation is completed, water (83g) and DCM (108g) are added, and the pH is adjusted to 6 with 1N hydrochloric acid, and the liquids are separated. The water layer is extracted with DCM (108g) again, and the organic phases are combined, and the organic phases are dried over anhydrous sodium sulfate and rotary concentrated to obtain hard foam Formula VI (15.1g, HPLC purity 95.3%). The chiral HPLC results of the product VI: R type purity 65.8%, S type purity 34.2%.

[0081] Part III Esterification

[0082] Example 10

[0083] At room temperature, first put 20g of Formula VI prepared in Example 2 and 166g of methanol into a three-necked flask, then slowly add 5.5g of concentrated sulfuric acid into the flask, replace with nitrogen 3 times, place in an oil bath, heat to reflux temperature while stirring, react for 4h, and confirm that the raw material reaction is complete by TLC. Cool to below 45°C, perform vacuum distillation, maintain the external temperature at 40-50°C, and distill to 1 / 3 of the initial volume. Then add 83g of water and 108g of DCM for extraction, and then separate the organic phase. Extract the organic phase with saturated sodium bicarbonate solution (100g*2 times), dry over anhydrous sodium sulfate, and concentrate to obtain a foamy solid Formula I (20.5g, HPLC purity 97.9%).

[0084] The characterization of compound I is as follows:

[0085] 1H NMR (400MHz, CDCl3) δ7.39 (d, J=8.6Hz, 1H), 7.14 (t, J=8.2Hz, 2H), 7.06–6.95 (m, 2H), 6. 88(td,J=7.9,4.9Hz,1H),6.76(dd,J=7.6,1.4Hz,1H),6.46(dd,J=8.2,2.0Hz,1H),6.42 (dd,J=8.1,2.1Hz,1H),6.37(t,J=2.3Hz,1H),4.86(t,J=7.3Hz,1H),3.90(s,3H),3.77( s,3H),3.68(s,3H),3.66–3.41(m,4H),3.07–2.70(m,5H),2.63(dd,J=14.6,7.8Hz,1H).

[0086] 13 CNMR(101MHz,CDCl3)δ171.45,160.65,155.59(d,J C-F =248.4Hz),153.56,152.64,134.22,132.43(d,J C-F =11.0Hz),128.95,128.90,124.00(q,J C-F =3.9Hz),123.85(q,J C-F =271.5Hz),123.55(d,J C-F =3.8Hz),123.44(q,J C-F =31.8Hz),122.74(d,J C-F =7.7Hz),120.59(d,J C-F =2.1Hz),115.14(d,J C-F =20.2Hz),112.13,109.41,105.12,103.10,56.14,55.32,51.86,49.10,46.09,40.15.

[0087] High resolution mass spectrum (ESI-HRMS): m / z = 587.2275 [M+H] + , Theoretical: 587.2276

[0088] Purity HPLC chart see Figure 3 ,Depend on Figure 3 It can be seen that the purity of the product compound I is 97.9%.

Claims

1. A racemization recovery method for the by-product of the resolution of a Letermovir intermediate, characterized in that: The racemization recovery method of the by-product of the splitting of the Letermovir intermediate comprises the following steps: 1) In the production process of letermovir, the mother liquor after the letermovir methyl ester shown in formula I is split by D-DTTA is concentrated under reduced pressure, and then L-DTTA is added to form a salt to obtain the letermovir methyl ester·L-DTTA salt shown in formula III; 2) suspending Temovir methyl ester·L-DTTA salt in methyl tert-butyl ether solvent, adding saturated sodium bicarbonate solution, stirring until the two phases are clear, separating the liquids, and concentrating the organic layer to obtain an oily substance, namely compound IV; 3) dispersing compound IV and potassium tert-butoxide with organic solvent A respectively to obtain a solution of compound IV and a suspension of potassium tert-butoxide, then controlling the temperature at 12-50° C., slowly dripping the solution of compound IV into the suspension of potassium tert-butoxide, and keeping the temperature to react to obtain an intermediate represented by formula V; after ensuring that all the raw materials have reacted, adding an appropriate amount of water without separation, raising the temperature to a temperature between 50° C. and reflux temperature to react, and separating to obtain compound VI after the reaction is completed; the organic solvent A is selected from one or more of dioxane, tetrahydrofuran, 2-methyltetrahydrofuran and ethylene glycol dimethyl ether; 4) Under the action of concentrated sulfuric acid, compound VI and methanol are subjected to an esterification reaction to obtain letermovir methyl ester as shown in formula I; The specific reaction is as follows: 。 2. The method for recovering the racemization of the by-product of the resolution of the Letermovir intermediate according to claim 1, characterized in that: In step 2), the mass volume ratio of letermovir methyl ester·L-DTTA salt: MTBE: saturated sodium bicarbonate is 1 g: (5-10) mL: (5-10) mL.

3. The method for recovering the racemization of the by-product of the resolution of the Letermovir intermediate according to claim 1, characterized in that: In step 3), the mass ratio of letermovir methyl ester·L-DTTA salt: organic solvent A: potassium tert-butoxide is 1:3-8:0.2-1.

4. The method for recovering the racemization of the by-product of the resolution of the Letermovir intermediate according to claim 1 or 3, characterized in that: In step 3), the temperature is controlled at 12-18° C., and the solution of compound IV is slowly dripped into the suspension of potassium tert-butoxide. After the dripping is completed, the temperature is kept to react until all the raw materials react to obtain the intermediate represented by formula V.

5. The method for recovering the racemization of the by-product of the resolution of the Letermovir intermediate according to claim 1, characterized in that: In step 3), water is added to the reaction system, and the temperature is raised to 50-60° C. and the reaction is maintained for 1-3 hours.

6. The method for recovering the racemization of the by-product of the resolution of the Letermovir intermediate according to claim 1 or 5, characterized in that: In step 3), the mass of water added to the reaction system is 0.2-3 times the mass of letermovir methyl ester·L-DTTA salt required for preparing the compound IV.

7. The method for recovering the racemization of the by-product of the resolution of the Letermovir intermediate according to claim 1, characterized in that: In step 3), the separation to obtain compound VI adopts the following steps: after the reaction is completed, the small bubbles gradually disappear or the liquid is difficult to evaporate in a water bath under reduced pressure at 50-60°C; after the distillation is completed, water and dichloromethane are added, the pH is adjusted to 5-6 with hydrochloric acid, the liquids are separated, the water layer is extracted with dichloromethane again, the organic phases are combined, the organic phases are dried over anhydrous sodium sulfate and rotary concentrated to obtain a hard foam compound VI.

8. The method for recovering the racemization of the by-product of the resolution of the Letermovir intermediate according to claim 1, characterized in that: Step 4) is specifically implemented as follows: concentrated sulfuric acid is slowly added to a methanol solution of compound VI, the temperature is raised to reflux temperature under a nitrogen atmosphere to react for 3-4 hours, and compound I is obtained after post-treatment.

9. The method for recovering the racemization of the by-product of the resolution of the Letermovir intermediate according to claim 1, characterized in that: Step 1) is specifically implemented as follows: the mother liquor is washed with a saturated sodium bicarbonate aqueous solution, the organic phase is dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a residue; the residue is dissolved in ethyl acetate and recrystallized with L-DTTA, and the crystals are dried to obtain Letermovir methyl ester·L-DTTA salt as shown in Formula III.

10. The compound represented by formula V,

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