A prostaglandin chiral intermediate and a process for its synthesis

Abstract

This invention relates to the field of chemical intermediates technology, specifically disclosing a chiral prostaglandin intermediate and its synthesis process. This invention provides a novel synthesis method for chiral prostaglandin intermediates, for example (…). R , E )-3-((tert-butyldiphenylsilyl)oxy)- N -Methoxy- N 4-Methylhexyl-enamide: This process is simple to operate, uses inexpensive raw materials, and has mild reaction conditions, making it suitable for industrial production. The addition of an ethylthio group side arm as a chiral auxiliary improves the chiral control and selectivity of the aldol condensation reaction. It also utilizes inexpensive and readily available ( ) R The formation of chirality is induced by the Evans chiral cofactor of 4-benzyl-2-oxazolidinone. In the Zhang enyne ring isomerization reaction, the catalyst prepared by (Sc,Rp)-Duanphos has high activity and reduces the amount of Rh metal, making the process cost-effective.

Description

[0001] This application is a divisional application of application filed on December 25, 2024, with application number 202411935975.3 and invention title "A chiral prostaglandin intermediate and its synthesis process". Technical Field

[0002] This invention relates to the field of pharmaceutical intermediate synthesis technology, specifically to a chiral prostaglandin intermediate and its synthesis process. Background Technology

[0003] Prostaglandins are a class of bioactive substances composed of unsaturated fatty acids, found in animals and humans, and possessing a variety of physiological functions. Their parent compound is prostatic acid, composed of a cyclopentane and two aliphatic side chains. Prostaglandins are present in almost all tissues and body fluids of mammals, and their impact on the female reproductive system is no less significant than that on the male. Their biological functions are extremely broad and complex, playing multiple important physiological roles in the body, involving the nervous, endocrine, reproductive, circulatory, and digestive systems. Based on their molecular structure, prostaglandins can be classified into types A, B, D, E, F, H, and I. They can now be prepared using biosynthetic or total synthetic methods and are used as drugs to treat diseases such as ulcers, glaucoma, early pregnancy, hypertension, and constipation.

[0004] To date, more than 20 prostaglandin analogs have been marketed worldwide. For nearly 50 years, developing efficient methods for synthesizing prostaglandins (PGs) has been a goal for synthetic chemists.

[0005] Patent CN 114262288 A reports a method for preparing a key intermediate, and the reaction equation is as follows:

[0006] The raw materials for the first step of this route are expensive, as are the metal catalysts and ligands. Furthermore, the effectiveness of the catalyst is greatly affected by the purity of the raw materials, making industrial-scale production impossible. This limits the application of this synthetic route. Summary of the Invention

[0007] To address the shortcomings of existing technologies, such as expensive raw materials, expensive catalysts and ligands, and the inability to conduct industrial-scale production, The first aspect of this invention provides a prostaglandin intermediate, as shown in Formula A:

[0008] R1 is selected from substituted or unsubstituted tert-butyl, substituted or unsubstituted benzyl; R3 is selected from , ; The R is selected from H or -SR. a The R a Selected from substituted or unsubstituted C1-C6 alkyl groups; The carbon atom marked with * is in the R configuration, or the S configuration, or is an achiral carbon atom.

[0009] A second aspect of this invention provides a synthetic process for a prostaglandin intermediate of formula VIII, comprising a compound of formula VII: Compound VII was added to the reaction system to obtain compound VIII; ; The reaction system is obtained by mixing N,N-dimethylpyridine, organic amine hydrochloride, 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride, and an organic solvent, and then adding N,N-diisopropylethylamine. or, The reaction system includes N,N'-carbonyldiimidazole, organic amine hydrochloride, triethylamine, and an organic solvent; R2 is selected from hydroxyl protecting groups; The hydroxyl protecting group is optionally a silicon-based protecting group, such as trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, diphenylmethylsilyl, diphenyltert-butylsilyl, or 2-tetrahydropyranyl.

[0010] The carbon atom marked with * is in the R configuration, or the S configuration, or is an achiral carbon atom.

[0011] A third aspect of this invention provides a synthetic process for a prostaglandin intermediate of formula VII, comprising a compound of formula VI: Compound VI dissociates when mixed with an acid to prepare compound VII; ; R2 is selected from hydroxyl protecting groups; R4 and R5 are each independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl. Wherein, the H on R4 or R5 may be optionally substituted or unsubstituted alkyl, substituted or unsubstituted fused-ring aryl, as exemplified but not limited to, structures such as [example structures would be inserted here]. ; The carbon atom marked with * is in the R configuration, or the S configuration, or is an achiral carbon atom; The acid is selected from hydrochloric acid, sulfuric acid, and phosphoric acid.

[0012] A fourth aspect of this invention provides a synthetic process for a prostaglandin intermediate of formula VI, comprising a compound of formula V. Hydrogen peroxide was added to the organic solution of compound V, followed by the addition of an aqueous solution of lithium hydroxide, and then extraction with an organic solvent. Compound V-1 was added to the extracted organic phase to obtain compound VI. ; R1 is selected from substituted or unsubstituted alkyl groups, and any H on R1 is substituted with an aryl group; R2 is selected from hydroxyl protecting groups; R4 and R5 are each independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl. Wherein, the H on R4 or R5 may be optionally substituted or unsubstituted alkyl, substituted or unsubstituted fused-ring aryl, and non-limiting examples include structures. ; The carbon atom marked with * is in the R configuration, or the S configuration, or is an achiral carbon atom.

[0013] The fifth aspect of this invention provides a synthetic process for a prostaglandin intermediate of formula V, comprising a compound of formula IV: Under an inert atmosphere, compound IV and imidazole are dissolved in an organic solvent, and tert-butyldiphenylchlorosilane is added to obtain compound V; ; R1 is selected from substituted or unsubstituted alkyl groups, and any H on R1 is substituted with an aryl group; The carbon atom marked with * is an R configuration, an S configuration, or an achiral carbon atom.

[0014] The sixth aspect of this invention provides a synthetic process for a prostaglandin intermediate of Formula IV, comprising a compound of Formula III: In an inert atmosphere, compound III is dissolved in an organic solvent, and then tri-n-butyltin hydride and azobisisobutyronitrile are added to prepare compound IV. ; The R is selected from -SR a The R a Selected from substituted or unsubstituted alkyl groups; R1 is selected from substituted or unsubstituted alkyl groups, and any H on R1 is substituted with an aryl group; The carbon atom marked with * is in the R configuration, or the S configuration, or is an achiral carbon atom.

[0015] The seventh aspect of this invention provides a process for synthesizing a prostaglandin intermediate of Formula III, comprising, Compound of Formula II The compound of formula II is mixed in an organic solvent, and then additives, N,N-diisopropylethylamine and crotonaldehyde are added to undergo a condensation reaction to obtain the compound of formula III. ; The additive is selected from one of titanium tetrachloride and dibutyl boron trifluoromethanesulfonate; When the additive is selected from titanium tetrachloride, N-methylpyrrolidone is also added to the organic solvent; The R is selected from -SR a The R a Selected from substituted or unsubstituted alkyl groups; R1 is selected from substituted or unsubstituted alkyl groups, and any H on R1 is substituted with an aryl group; The carbon atom marked with * is an R configuration, an S configuration, or an achiral carbon atom.

[0016] In some specific embodiments of the synthesis process of prostaglandin intermediates proposed in the seventh aspect, When compound I is added to the reaction system, the reaction yields compound II. ; The reaction system comprises an organic solvent, a 2-oxazolidinone derivative, 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride, 4-dimethylaminopyridine, and N,N-diisopropylethylamine. or, The reaction system includes an organic solvent and N,N'-carbonyldiimidazole; The R is selected from -SR a The R a Selected from substituted or unsubstituted C1-C6 alkyl groups; R1 is selected from substituted or unsubstituted C1~C4 alkyl groups, and any H on R1 is substituted with an aryl or alkyl group; The carbon atom marked with * is an R configuration, an S configuration, or an achiral carbon atom.

[0017] In some specific embodiments of the synthesis process of prostaglandin intermediates proposed in the seventh aspect, Compound Ic was reacted with n-butyllithium, ( R )-4-benzyl-2-oxazolidinone, when dissolved together in an organic solvent, yields compound II-c, such as:

[0018] The eighth aspect of this invention provides a process for synthesizing a prostaglandin intermediate of Formula X, comprising, Compound of formula IX, In an inert atmosphere, the compound of formula IX dissolves in an organic solvent, and upon the addition of a catalyst, reacts to yield a product with structure X, such as:

[0019] R2 is selected from hydroxyl protecting groups; The hydroxyl protecting group is optionally a silicon-based protecting group, such as trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, diphenylmethylsilyl, diphenyltert-butylsilyl, or 2-tetrahydropyranyl; The catalyst [Rh(( Sc,Rp The preparation method of [-DuanPhos)(COD)]SbF6 is as follows: a metal precursor is mixed with an additive to form a mixed system, and a ligand is added to the mixed system to obtain the catalyst. The structure of the ligand is as follows:

[0020] The metal precursor is [Rh(COD)Cl]2; The additive is AgSbF6; The organic solvent is selected from dichloromethane, 1,2-dichloroethane, chloroform, and chlorobenzene. When dichloromethane, 1,2-dichloroethane, chloroform, and chlorobenzene are used as solvents in Example 9 of the present invention, the yields are 91%, 95%, 92%, and 86%, respectively.

[0021] All reagents used in this invention are purchased from the open and legal market and have not undergone further purification.

[0022] In this embodiment of the invention: The structure is selected from one of VI-a, VI-b, VI-c, and VI-d; In this invention, the room temperature is 5~40℃. In some embodiments, the room temperature is 10~35℃. In some embodiments, the room temperature is 15~30℃. In some embodiments, the room temperature is 20~25℃. In some embodiments, the room temperature is 25℃.

[0023] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon group, the carbon ring of which may contain 3 to 20 carbon atoms, preferably 3 to 12 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12) carbon atoms, and more preferably 3 to 6 carbon atoms. The partially unsaturated monocyclic or polycyclic cyclic hydrocarbon group is a saturated cycloalkyl group or may optionally contain one, two, or more double and / or triple bonds on its ring, thereby forming a so-called cycloalkenyl or cycloynyl group.

[0024] Advantages of this invention: This invention provides a novel synthesis method for chiral prostaglandin intermediates, for example ( R , E )-3-((tert-butyldiphenylsilyl)oxy)- N -Methoxy- N -Methylhexyl-4-enamide, this process is simple to operate, uses inexpensive raw materials, and has mild reaction conditions, making it suitable for industrial production, especially the ligand in the catalyst used in Example 9 ( S c, R p)-Duanphos exhibits better activity than existing technologies using (S)-BINAP ligands, significantly reduces Rh metal usage, and unexpectedly lowers production costs. The addition of an ethylthio side arm as a chiral auxiliary improves the chiral control and selectivity of the aldol condensation reaction, and utilizes inexpensive and readily available (p)-Duanphos ligands. R The use of the Evans chiral cofactor of 4-benzyl-2-oxazolidinone to induce chirality gives the process a cost advantage, with the estimated material cost of intermediate product compound X at around 10,000 yuan / kg. Attached Figure Description

[0025] Figure 1 The NMR spectrum of compound III-a is shown. Detailed Implementation

[0026] The technical solutions of the present invention will be clearly and completely described below with reference to the embodiments and accompanying drawings. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0027] This invention provides a process for synthesizing chiral intermediates of prostaglandins. The process flow is as follows:

[0028] This invention provides a synthetic process for a prostaglandin intermediate, comprising the following steps: In the first step, the acetic acid derivative and the 2-oxazolidinone derivative undergo a condensation reaction to prepare compound II; In the second step, compound II undergoes an aldol condensation reaction with crotonaldehyde to prepare compound III; In the third step, compound III undergoes a free radical reaction, losing its side chain to obtain compound IV; In the fourth step, compound IV undergoes a substitution reaction with tert-butyldiphenylchlorosilane to obtain compound V; In the fifth step, compound V is hydrolyzed under alkaline conditions to form a carboxylic acid, which is then co-crystallized with di(cyclohexyl)amine to obtain compound VI; Step 6: Compound VI dissociates under acidic conditions to remove di(cyclohexyl)amine, yielding compound VII; In step seven, compound VII undergoes a condensation reaction with dimethylhydroxylamine hydrochloride to prepare compound VIII.

[0029] Example 1

[0030] First, after purging the reactor (10 L) with nitrogen for 10-20 minutes, add dichloromethane (1 L) to the reactor. Transfer (R)-4-benzyl-2-oxazolidinone (550.0 g), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (595.0 g) and 4-dimethylaminopyridine (37.92 g) to the reactor under nitrogen protection using dichloromethane (2.3 L). Start stirring and add N,N-diisopropylethylamine (1350 mL).

[0031] Compound Ia (373.0 g) was slowly added dropwise to the reaction system through a constant-pressure dropping funnel under nitrogen protection; the temperature was controlled to below 30°C. After the addition of compound Ia, the mixture was stirred at room temperature for 10 hours. Subsequently, 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (178.5 g), 4-dimethylaminopyridine (15.2 g), and compound Ia (93.0 g) were added to the reaction system. After the addition, the mixture was stirred at room temperature for 10 hours. After the reaction was completed, the reaction system was cooled to 0°C, and a dilute hydrochloric acid aqueous solution (2 M, 3 L) was added to the reaction system. After vigorous stirring for 10 minutes, the mixture was separated, and the organic phase was washed successively with a dilute hydrochloric acid aqueous solution (2 M, 1 L) and a saturated sodium bicarbonate aqueous solution (1 L). Combine the organic phases, dry with anhydrous sodium sulfate, filter, evaporate the solvent, and perform rapid column chromatography on the residue (ethyl acetate: petroleum ether = 1:10). Collect the organic phase, evaporate the solvent, and obtain compound II-a (yield: 78.4%, purity: 98.40%).

[0032] 1 H NMR (400 MHz, Chloroform- d ) δ 7.36 – 7.17 (m, 5H), 4.67 (ddt, J =9.3, 7.7, 3.2 Hz, 1H), 4.24 – 4.12 (m, 2H), 3.93 – 3.74 (m, 2H), 3.26 (dd, J= 13.5, 3.4 Hz, 1H), 2.80 (dd, J = 13.5, 9.3 Hz, 1H), 2.64 (q, J = 7.4 Hz, 2H), 1.28 (t, J = 7.4 Hz, 3H). 13 C NMR (101 MHz, Chloroform- d ) δ 169.29, 153.18, 135.20, 129.50,129.50, 128.94, 128.94, 127.34, 66.25, 55.10, 37.64, 34.13, 26.23, 14.36.

[0033] The second step involves purging the reactor (10 L) with nitrogen for 10-20 minutes, then maintaining nitrogen protection throughout the reactor. Compound II-a (679 g) is dissolved in dichloromethane (DCM, 4.2 L) and transferred to the reactor. When the temperature inside the reactor drops to -20°C, titanium tetrachloride (484.1 g) is added dropwise, with the temperature controlled below -20°C.

[0034] After adding titanium tetrachloride, the mixture was kept warm and stirred for half an hour. Then, N,N-diisopropylethylamine (471.2 g) was added dropwise, with the temperature controlled between -20℃ and -30℃.

[0035] After adding N,N-diisopropylethylamine, the mixture was kept at this temperature and stirred for half an hour. Then, N-methylpyrrolidone (241.0 g) was added dropwise, with the temperature maintained between -20°C and -30°C. After adding N-methylpyrrolidone, the mixture was kept at this temperature and stirred for half an hour. Then, crotonaldehyde (255.6 g) was added dropwise, with the temperature maintained below -30°C.

[0036] After the addition of crotonaldehyde, the reaction was maintained at this temperature for 1 hour. After the reaction was completed, the reaction system was heated to -20°C, and an aqueous solution of ammonium chloride (12 wt%, 3 L) was added to quench the reaction. The temperature was then raised to room temperature, and the mixture was stirred vigorously for 10 minutes. After standing, the mixture was separated into liquid and liquid phases. The organic phase was washed again with an aqueous solution of ammonium chloride (12 wt%, 1 L), dried over anhydrous sodium sulfate, and the solvent was evaporated to obtain compound III-a (yield: 95.1%).

[0037] 1 H NMR (400 MHz, Chloroform- d ) δ 7.40 – 7.25 (m, 5H), 5.85 (dtd,J =16.1, 6.5, 0.9 Hz, 1H), 5.60 – 5.49 (m, 1H), 4.85 (d, J = 8.1 Hz, 1H), 4.73(ddt, J = 9.3, 7.2, 3.6 Hz, 1H), 4.47 (t, J = 7.6 Hz, 1H), 4.26 – 4.17 (m,2H), 3.28 (dd, J = 13.5, 3.5 Hz, 1H), 2.83 (ddd, J = 12.2, 8.3, 6.4 Hz, 2H), 2.79 – 2.71 (m, 1H), 1.73 (dd, J = 6.5, 1.7 Hz, 3H), 1.31 (t, J = 7.4 Hz, 3H). (The active hydrogen on the hydroxyl group did not elute.)

[0038] In the third step, after purging the reactor (10 L) with nitrogen for 10-20 minutes, the reactor was kept under nitrogen protection throughout. Compound III-a (849.0 g) was dissolved in toluene (5.0 L) and transferred to the reaction vessel. Nitrogen was bubbled through the bottom of the reactor to remove air from the solvent for 1 hour. Tri-n-butyltin hydride (848.6 g) and azobisisobutyronitrile (79.8 g) were added, and bubbling was continued for another 10 minutes. The temperature was raised to 85°C and maintained for 1.5 hours. After the reaction was completed, the solvent was evaporated. Heptane-1 (1 L) was added to the residue, stirred for 10 minutes, allowed to stand for 20 minutes, and the upper organic phase was poured off. Heptane-2 (500 mL) was added to the residue, and the above operation was repeated twice. The residue was dissolved in isopropanol (990 mL) and transferred to the reactor, and heptane-3 (990 mL) was added dropwise. The mixture was cooled to 0°C and seed crystals IV-a (5 g) were added. The mixture was stirred until a large amount of solid precipitated. Then, n-heptane-3 (1.98 L) was added dropwise. After the addition was complete, the mixture was kept at 0°C and stirred for 3 hours. The mixture was filtered under reduced pressure, and the filter cake was washed with solvent (isopropanol:n-heptane = 1:6, 200 mL). The filter cake was dried under vacuum to obtain a yellow solid compound IV-a (yield: 70.3%, purity: 96.76%).

[0039]

[0040] In the fourth step, the three-necked flask (2 L) was purged with nitrogen. Under nitrogen protection, compound IV-a (105 g), imidazole (29.7 g), and dichloromethane (1 L) were added sequentially. The reaction system was then cooled to 0 °C. Tert-butyldiphenylchlorosilane (104.7 g) was added dropwise, maintaining the temperature below 10 °C. After the addition of tert-butyldiphenylchlorosilane was complete, the temperature was raised to room temperature and reacted for 2 hours. The reaction solution was filtered under reduced pressure using diatomaceous earth. The filter cake was washed with dichloromethane (50 mL × 3). The organic phase was washed sequentially with saturated ammonium chloride aqueous solution (100 mL × 2) and saturated sodium chloride aqueous solution (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered under reduced pressure, and the solvent was evaporated to obtain compound Va (yield: 95%).

[0041] 1 H NMR (400 MHz, Chloroform- d ) δ 7.84 – 7.75 (m, 4H), 7.44 (dt, J =8.5, 6.3 Hz, 6H), 7.40 – 7.20 (m, 5H), 5.56 (ddd, J = 15.3, 7.7, 1.8 Hz, 1H),5.41 – 5.27 (m, 1H), 4.84 (q, J = 6.8 Hz, 1H), 4.59 (ddt, J = 10.5, 6.8, 3.1Hz, 1H), 4.16 – 4.03 (m, 2H), 3.40 (dd, J = 15.7, 7.0 Hz, 1H), 3.25 (td, J =15.7, 14.5, 7.9 Hz, 2H), 2.70 (dd, J = 13.4, 9.6 Hz, 1H), 1.54 (dd, J = 6.5,1.6 Hz, 3H), 1.17 – 1.11 (m, 9H). 13 C NMR (101 MHz, Chloroform- d) δ 170.31, 153.35, 136.14, 136.14,136.05, 136.05, 135.48, 134.23, 134.19, 132.80, 129.63, 129.55, 129.46,129.46, 129.00, 129.00, 127.53, 127.53, 127.40, 127.40, 127.35, 127.31,71.25, 66.02, 55.12, 44.26, 37.82, 27.10, 27.10, 27.10, 19.39, 17.49.

[0042] In step 5, compound Va (235.0 g) was dissolved in tetrahydrofuran (1175 mL) and transferred to a three-necked reaction flask (3 L). Nitrogen gas was purged, and the mixture was cooled to 0°C. Hydrogen peroxide solution (30% aq., 232.2 g) was added, followed by dropwise addition of a water solution of LiOH·H₂O (29.9 g) (588 mL), while maintaining the temperature below 5°C. After the addition of the lithium hydroxide solution, the reaction mixture was stirred and kept at this temperature for 2 hours. After the reaction was complete, the reaction system was cooled to 0°C, and sodium bisulfite (40% aq., 100 mL) was added dropwise to quench the reaction. The temperature was maintained below 15°C, and the mixture was stirred for 30 minutes. The complete quenching of the hydrogen peroxide was checked using starch-potassium iodide test paper. The mixture was concentrated under reduced pressure to remove most of the tetrahydrofuran. Subsequently, methyl tert-butyl ether (1 L) was added to the aqueous phase, stirred, allowed to stand, and then separated. The aqueous phase was then extracted with methyl tert-butyl ether (500 mL), and the organic phases were combined and dried over anhydrous sodium sulfate. The mixture was filtered and the filtrate was collected.

[0043] Under the conditions shown in Table 1, alkylamine (0.11 mol) was added dropwise to the filtrate for the first time, followed by seed crystals (1 g), resulting in the precipitation of a large amount of solid. Alkylamine (0.33 mol) was then added dropwise a second time. After the addition was complete, stirring was continued for 12 hours. The mixture was filtered under reduced pressure, and the filter cake was washed with solvent (methyl tert-butyl ether: n-heptane = 1:5, 250 mL). The filter cake was then vacuum dried. Experiments were conducted in groups 1 through 4, and the yield (%) and purity (%) of the product were measured.

[0044] Table 1: ; The reaction formula for step six is ​​as follows: Step 6: Disperse any one of compounds VI-a, VI-b, VI-c, or VI-d (207 g) as a substrate in ethyl acetate (1.5 L), and add dropwise an aqueous solution of concentrated sulfuric acid (36.9 g) (800 mL), maintaining the temperature below 25°C. Stir vigorously for 1 hour until the solution becomes clear. After standing for 30 minutes, separate the liquids. Add an aqueous solution of concentrated sulfuric acid (14.77 g) (400 mL) to the organic phase. Stir vigorously for 30 minutes, let stand, and separate the liquids. Wash the organic phase sequentially with water (200 mL), saturated sodium bicarbonate solution (200 mL), and saturated saline solution (200 mL). Dry the organic phase with anhydrous sodium sulfate, filter through a diatomaceous earth sieve, evaporate the solvent, and prepare groups 5-8 to obtain product compound VII-a. The yield (%) and purity (%) are shown in Table 2.

[0045] Table 2: ; The NMR data for VII-a are as follows: 1 H NMR (400 MHz, Chloroform- d ) δ 11.61 (s, 1H), 7.75 (ddq, J = 8.1,3.2, 1.6 Hz, 4H), 7.52 – 7.39 (m, 6H), 5.50 (ddt, J = 15.2, 7.5, 1.7 Hz, 1H),5.40 – 5.27 (m, 1H), 4.63 (q, J = 6.6, 6.1 Hz, 1H), 2.73 – 2.62 (m, 1H), 2.58– 2.48 (m, 1H), 1.55 (dd, J = 6.4, 1.9 Hz, 3H), 1.17 – 1.04 (m, 9H). 13 C NMR (101 MHz, Chloroform- d ) δ 177.31, 136.09, 136.09, 135.98,135.98, 133.99, 133.84, 132.14, 129.73, 129.59, 127.58, 127.58, 127.58,127.42, 127.42, 71.52, 43.61, 27.02, 27.02, 27.02, 19.34, 17.48.

[0046] Step 7: Purge the reaction vessel (2 L) with nitrogen for 10 minutes, add N,N-dimethylpyridine (4.5 g), dimethylhydroxylamine hydrochloride (44.5 g), and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (87.4 g), dissolve in dichloromethane (500 mL), cool to 10°C, then add N,N-diisopropylethylamine (137.5 g) dropwise, maintaining the temperature below 10°C. Dissolve compound VII-a (140.0 g) in dichloromethane (200 mL) and slowly add it dropwise to the reaction system, maintaining the temperature below 10°C. After the addition of compound VII-a, raise the temperature to room temperature and stir for 16 hours. After the reaction is complete, add dichloromethane (400 mL) and dilute hydrochloric acid (700 mL, 2 M) to the reaction solution, stir vigorously for 10 minutes, let stand, and separate the contents. The organic phase was then washed successively with dilute hydrochloric acid (300 mL, 2 M), saturated sodium bicarbonate aqueous solution (300 mL), and saturated brine (200 mL). The organic phase was dried with anhydrous sodium sulfate, filtered, and the solvent was evaporated to obtain compound VIII-a (yield: 96%, purity: 95%, chiral purity: 95%).

[0047] 1 H NMR (400 MHz, Chloroform- d ) δ 7.72 (tt, J = 6.2, 1.7 Hz, 4H), 7.40(dtq, J = 11.1, 6.4, 2.1 Hz, 6H), 5.48 (ddt, J = 15.3, 7.4, 1.7 Hz, 1H), 5.36– 5.23 (m, 1H), 4.75 (q, J = 7.0 Hz, 1H), 3.61 (s, 3H), 3.14 (s, 3H), 2.87(dd, J = 14.8, 7.0 Hz, 1H), 2.53 (dd, J = 14.5, 6.5 Hz, 1H), 1.50 (dd, J =6.5, 1.6 Hz, 3H), 1.09 (s, 9H). 13 C NMR (101 MHz, Chloroform- d) δ 171.66, 136.04, 136.04, 136.00,136.00, 134.35, 134.16, 133.00, 129.54, 129.41, 127.45, 127.45, 127.31,127.31, 126.72, 71.63, 61.22, 40.84, 31.96, 27.04, 27.04, 27.04, 19.35,17.48. Example 2: (Synthesis of compound II-b)

[0048] In the first step, (R)-4-benzyl-2-oxazolidinone (12.0 g), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (19.47 g), and 4-dimethylaminopyridine (827.3 mg) were added to a reaction flask, dissolved in dichloromethane (120 mL), and purged with nitrogen. N,N-diisopropylethylamine (21.9 g) was added; compound Ia (8.63 g) was added dropwise; the temperature was maintained below 20 °C. After the addition of compound Ia, the mixture was stirred at room temperature for 16 hours. After the reaction was complete, the reaction system was cooled to 0 °C, and a dilute hydrochloric acid aqueous solution (2 M, 60 mL) was added to the reaction system. After vigorous stirring for 10 minutes, the mixture was separated. The organic phase was washed successively with a dilute hydrochloric acid aqueous solution (2 M, 50 mL) and a saturated sodium bicarbonate aqueous solution (50 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated. The residue was subjected to rapid column chromatography (ethyl acetate: petroleum ether = 1:9), the eluent was collected, the solvent was evaporated, and compound II-b was obtained (yield: 67%, purity: 98.23%).

[0049] Example 3: (Synthesis of compound II-c)

[0050] The first step is to add compound Ic, ( R35.0 g of 4-benzyl-2-oxazolidinone was added to a reaction flask, followed by 350 mL of dichloromethane solvent. The mixture was cooled to -60 °C, and 99 mL of 2.4 M butyllithium was added dropwise. The temperature was maintained below -60 °C, and the mixture was stirred for half an hour. 24.5 g of chloroacetyl chloride was added dropwise, and the temperature was maintained below -50 °C. The reaction was then maintained at -50 °C for 1 hour. After the reaction was complete, the reaction was quenched with 150 mL of saturated ammonium chloride aqueous solution. The organic phase was washed successively with 150 mL of saturated ammonium chloride aqueous solution, 100 mL of saturated sodium bicarbonate aqueous solution, and 50 mL of saturated brine. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated. The residue was subjected to rapid column chromatography (ethyl acetate: petroleum ether = 1:5), and the eluent was collected. The solvent was evaporated to obtain compound II-c (yield: 85%, purity: 96.35%). Example 4: (Synthesis of compound II-d)

[0051] The first step is to ( R 4-tert-butyl-2-oxazolidinone (5.0 g), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (10.0 g), and 4-dimethylaminopyridine (426.6 mg) were added to a reaction flask, dissolved in dichloromethane (50 mL), and purged with nitrogen. N,N-diisopropylethylamine (11.3 g) was added; compound Ia (5.5 g) was added dropwise; the temperature was maintained below 20 °C. After the addition of compound Ia, the mixture was stirred at room temperature for 16 hours. After the reaction was complete, the reaction system was cooled to 0 °C, and a dilute hydrochloric acid aqueous solution (2 M, 25 mL) was added to the reaction system. After vigorous stirring for 10 minutes, the mixture was separated. The organic phase was washed successively with a dilute hydrochloric acid aqueous solution (2 M, 20 mL) and a saturated sodium bicarbonate aqueous solution (20 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated. The residue was subjected to rapid column chromatography (ethyl acetate: petroleum ether = 1:9), the eluent was collected, the solvent was evaporated, and compound II-d was obtained (yield: 83%, purity: 97.23%). Example 5: (Second synthetic method for compound II-a)

[0052] Compound Ia (44.1 g) was added to a reaction flask, followed by dichloromethane (500 mL) as solvent. The mixture was cooled to 0°C, and N,N'-carbonyldiimidazole (67.8 g) was added. The reaction was maintained at this temperature for 2 hours. (Added...) R50.0 g of 4-benzyl-2-oxazolidinone was stirred at this temperature for half an hour, then the mixture was heated to room temperature and reacted for 12 hours. After the reaction was complete, the reaction system was cooled to 0°C, and 200 mL of dilute hydrochloric acid solution (2 M) was added to the reaction system. The mixture was stirred vigorously for 10 minutes, and then separated. The organic phase was washed successively with 200 mL of dilute hydrochloric acid solution (2 M) and 100 mL of saturated sodium bicarbonate solution. The organic phase was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated. The residue was subjected to rapid column chromatography (ethyl acetate: petroleum ether = 1:5), the eluent was collected, and the solvent was evaporated to obtain compound II-a (yield: 76%, purity: 97.37%). Example 6: (Second synthetic method for compound III-a)

[0053] In the second step, compound II-a (10.0 g) was added to the reaction flask, followed by dichloromethane (150 mL) as solvent. Nitrogen gas was then added to displace the nitrogen gas, and the temperature was lowered to -40°C. Dibutylboron trifluoromethanesulfonate (1 M, 43.2 mL) was added dropwise, and the temperature was maintained below -40°C with stirring for half an hour. N,N-diisopropylethylamine (44.6 g) was added dropwise, and the temperature was maintained below -40°C with stirring for half an hour. The temperature was lowered to -78°C, and crotonaldehyde (3.8 g) was added dropwise, maintaining the temperature below -70°C. The mixture was stirred for half an hour, then the temperature was raised to -40°C, and the reaction was stirred for 1 hour. After the reaction was complete, the reaction system was heated to -20°C, and ammonium chloride aqueous solution (12... wt Quench the reaction with 60 mL of ammonium chloride solution, heat to room temperature, stir vigorously for 10 minutes, let stand, and separate the liquids. The organic phase is then sequentially quenched with ammonium chloride aqueous solution (12... wt The organic phase was washed with saturated sodium bicarbonate aqueous solution (10 mL) and saturated saline solution (10 mL). The organic phase was dried over anhydrous sodium sulfate and the solvent was evaporated. The residue was subjected to rapid column chromatography (ethyl acetate: petroleum ether = 1:5), the eluent was collected, the solvent was evaporated, and compound III-a was given (yield: 84%, purity: 99.17%).

[0054] Example 7: (Second synthetic method for compound VIII-a)

[0055] Compound VII-a (50.0 g) was added to a reaction flask, followed by dichloromethane (500 mL) as solvent. The mixture was cooled to 0°C, and N,N'-carbonyldiimidazole (26.2 g) and triethylamine (24.7 g) were added. The reaction was maintained at this temperature for 2 hours. Dimethylhydroxylamine hydrochloride (15.9 g) was then added, and the mixture was stirred at this temperature for half an hour. The temperature was then raised to room temperature, and the reaction was continued for 12 hours. After the reaction was complete, the reaction system was cooled to 0°C, and dilute hydrochloric acid aqueous solution (2 M, 200 mL) was added to the reaction system. The mixture was stirred vigorously for 10 minutes, and the liquid was separated. The organic phase was washed successively with dilute hydrochloric acid aqueous solution (2 M, 200 mL) and saturated sodium bicarbonate aqueous solution (100 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated. The residue was subjected to rapid column chromatography (ethyl acetate: petroleum ether = 1:5), and the eluent was collected. The solvent was evaporated to obtain compound VIII-a (yield: 84%, purity: 98.16%).

[0056] Example 8

[0057] After purging the 20 L reactor with nitrogen for 10-20 minutes, cooling was initiated. Compound XII (227.1 g) and N,N,N',N'-tetramethylethylenediamine (53.4 mL) were dissolved in methyl tert-butyl ether (5 L) and added to the reactor under micro-nitrogen purging protection. Stirring was started, and the temperature was lowered to -25 to -30 °C under micro-nitrogen purging protection. A solution of n-butyllithium in n-hexane (2.5 M, 1.1 L) was added dropwise to the system through a constant-pressure dropping funnel under micro-nitrogen purging protection. After the addition was complete, the system was kept at -20 °C and stirred for 1 hour. The temperature inside the reactor was controlled below -20 °C, and a mixed solution of compound VIII (733 g) and methyl tert-butyl ether (2.3 L) was added dropwise. After the addition was complete, the system was heated to -10 to 0 °C and stirred for 1 hour. After the reaction was completed, the reaction system was cooled to -20 to -10 °C. A dilute hydrochloric acid solution (1.2 M, 3.36 L) was added to the reaction system in one go. After vigorous stirring for 5 minutes, the mixture was allowed to stand and separated. The lower aqueous phase was discharged, and the organic phase was washed with a saturated sodium bicarbonate aqueous solution (2.2 L). After stirring for 5 minutes, the mixture was allowed to stand and separated. The organic phase was dried with anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure at 40 °C. The residue was dissolved in n-heptane (2.5 L) and cooled to 0 °C. The mixture was stirred overnight, filtered, and the filtrate was collected. The filtrate was then cooled to -20 °C, and seed compound IX (5 g) was added. The mixture was stirred overnight, filtered at low temperature, and the filter cake was washed with cooled n-heptane (-20 °C). The mixture was then dried under vacuum at room temperature to obtain compound IX (yield: 90%, purity: 98.64%, chiral purity: 97.10%).

[0058] Example 9 Catalyst preparation steps: Weigh 100 mg of the metal precursor (1,5-cyclooctadiene) rhodium chloride (I) dimer and 139 mg of silver hexafluoroantimonate, dissolve them in 20 mL of ultra-dry acetone, purge with nitrogen three times, and stir at room temperature for half an hour. Under nitrogen atmosphere, filter out the solids from the solution, and add the ligand ( Sc,Rp )-DuanPhos (160 mg), after nitrogen purging three times and stirring at room temperature for half an hour, the solvent was then removed using an oil pump, and the prepared catalyst [Rh(( Sc,Rp Store )-DuanPhos)(COD)]SbF6 in a glove box.

[0059] Preparation steps of compound X: Weigh out compound IX (200.0 g), and prepare the catalyst [Rh(( Sc,Rp [160 mg, 0.005 eq.]SbF6 was added to a 5 L round-bottom flask, and 2.0 L of distilled 1,2-dichloroethane was added as solvent. After purging with nitrogen three times, the mixture was heated to 60 °C and reacted for 3 hours. After the reaction was completed, the solvent was removed by concentration, and the crude product was diluted with 2.0 L of n-heptane. Column chromatography (petroleum ether: ethyl acetate = 20:1) was performed, and the eluent was collected and concentrated under reduced pressure at 40 °C to obtain compound X (yield: 95%, purity: 98.32%).

[0060] Comparative Example 1 The ligand types and metal precursors in the catalyst preparation step of Example 9, and the solvent types in the preparation step of compound X, were replaced with the conditions shown in Table 3 to produce groups 1 to 15. The results are shown in Table 3. Table 3 ; In Table 3, " / " indicates that it is the same as implementation 9; It will be apparent to those skilled in the art that the present invention is not limited to the details of the exemplary embodiments described above, and that the invention can be implemented in other specific forms without departing from its spirit or essential characteristics. Therefore, the embodiments should be considered in all respects as exemplary and non-limiting, and the scope of the invention is defined by the appended claims rather than the foregoing description. Thus, all variations falling within the meaning and scope of equivalents of the claims are intended to be included within the present invention. No reference numerals in the claims should be construed as limiting the scope of the claims.

[0061] Furthermore, it should be understood that although this specification describes embodiments, not every embodiment contains only one independent technical solution. This narrative style is merely for clarity. Those skilled in the art should consider the specification as a whole, and the technical solutions in each embodiment can also be appropriately combined to form other embodiments that can be understood by those skilled in the art.

Claims

1. A prostaglandin intermediate, such as formula A: ； R1 is selected from substituted or unsubstituted tert-butyl, substituted or unsubstituted benzyl; said R3 is selected from , ; said R is selected from H or -SR a , said R a is selected from substituted or unsubstituted C1-C6alkyl; The carbon atom marked with * is in the R configuration, or the S configuration, or is an achiral carbon atom.

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