Prostaglandin chiral intermediate and synthesis process thereof

Abstract

The invention relates to the technical field of chemical intermediates, particularly discloses a prostaglandin chiral intermediate and a synthesis process thereof, and provides synthesis of a novel prostaglandin chiral intermediate, for example, (R, E)-3-((tert-butyldiphenylsilyl) oxy)-N-methoxy-N-methylhexyl-4-enamide. The process is simple to operate, cheap in raw material, mild in reaction condition and suitable for industrial production, an ethylthio side arm is increased by a chiral auxiliary agent, so that the chiral control selectivity of aldol condensation reaction is better, a cheap and easily available (R)-4-benzyl-2-oxazolidinone Evans chiral auxiliary group is used for inducing chiral formation, and (Sc, Sb)-2-oxazolidinone is used in Zhang eneyne ring isomerization reaction. The catalyst prepared from (Rp, Rp)-Duanphos is high in activity, and the dosage of Rh metal is reduced, so that the process has the cost advantage.

Description

Technical Field

[0001] The present invention relates to the technical field related to the synthesis of pharmaceutical intermediates, in particular to a prostaglandin chiral intermediate and a synthesis process thereof. Background Art

[0002] Prostaglandins are active substances composed of unsaturated fatty acids that exist in animals and humans and have multiple physiological effects. Their parent compound is prostatic acid, which consists of a cyclopentane and two aliphatic side chains. Prostaglandins exist in almost all tissues and body fluids of mammals, and their effects on the female reproductive system are no less than those on the male. Its biological effects are extremely extensive and complex, and it plays a variety of important physiological functions in the body, involving the nervous system, endocrine system, reproductive system, circulatory system, digestive system and other aspects. According to different molecular structures, prostaglandins can be divided into types A, B, D, E, F, H, and I. At present, they can be prepared by biosynthesis or total synthesis, and used as drugs to treat diseases such as ulcers, glaucoma, early pregnancy, hypertension and constipation.

[0003] So far, more than 20 prostaglandin analogs have been marketed worldwide. For nearly 50 years, developing efficient methods for synthesizing PGs has been the goal of synthetic chemists.

[0004] Patent CN 114262288 A reports the preparation method of the key intermediate, and the reaction equation is as follows:

[0005]

[0006] The raw materials for the first step of this route are expensive, the metal catalyst and the ligand are expensive, and the effect of the catalyst is greatly affected by the purity of the raw materials, so it is impossible to carry out industrial production, thus limiting the application of this synthetic route. Summary of the invention

[0007] In view of the shortcomings of the above prior art, such as expensive raw materials, expensive catalysts and ligands, and inability to carry out industrial production,

[0008] The first aspect of the present invention provides a prostaglandin intermediate, such as formula A:

[0009]

[0010] The R1 is selected from substituted or unsubstituted tert-butyl, substituted or unsubstituted benzyl;

[0011] The R3 is selected from

[0012] The R is selected from H or -SR a , the R aSelected from substituted or unsubstituted C1-C6 alkyl;

[0013] The carbon atom marked with * is an R configuration, an S configuration, or an achiral carbon atom.

[0014] The second aspect of the present invention provides a synthesis process of a prostaglandin intermediate represented by formula VIII, comprising a compound of formula VII:

[0015] Adding compound VII to the reaction system to obtain a compound of formula VIII;

[0016]

[0017] The reaction system is prepared by mixing N,N-dimethylpyridine, organic amine hydrochloride, 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride and an organic solvent, and then adding N,N-diisopropylethylamine.

[0018] or,

[0019] The reaction system comprises N,N'-carbonyldiimidazole, organic amine hydrochloride, triethylamine and an organic solvent;

[0020] Said R2 is selected from a hydroxyl protecting group;

[0021] The hydroxy protecting group is optionally a silicon protecting group, such as any of trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, diphenylmethylsilyl, diphenyltert-butylsilyl, or 2-tetrahydropyranyl.

[0022] The carbon atom marked with * is an R configuration, an S configuration, or an achiral carbon atom.

[0023] The third aspect of the present invention provides a synthesis process of a prostaglandin intermediate represented by formula VII, comprising a compound of formula VI:

[0024] The compound of formula VI is mixed with an acid to dissociate to obtain a compound of formula VII;

[0025]

[0026] Said R2 is selected from a hydroxyl protecting group;

[0027] The R4 and R5 are each independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl,

[0028] Wherein, the H on R4 or R5 is optionally substituted by a substituted or unsubstituted alkyl group, a substituted or unsubstituted condensed ring aromatic group, and the non-limiting exemplary structures are as follows,

[0029] The carbon atom marked with * is an R configuration, an S configuration, or an achiral carbon atom;

[0030] The acid is selected from one of hydrochloric acid, sulfuric acid and phosphoric acid.

[0031] In a fourth aspect, the present invention provides a synthesis process of a prostaglandin intermediate represented by formula VI, comprising: a compound of formula V Hydrogen peroxide is added to an organic solution of the compound of formula V, followed by dropwise addition of an aqueous lithium hydroxide solution, followed by extraction with an organic solvent, and the compound of formula V-1 is added to the extracted organic phase to obtain a compound of formula VI;

[0032]

[0033] The R1 is selected from substituted or unsubstituted alkyl, and any H on the R1 is substituted by an aryl group;

[0034] Said R2 is selected from a hydroxyl protecting group;

[0035] The R4 and R5 are each independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl,

[0036] Wherein, the H on R4 or R5 is optionally substituted by a substituted or unsubstituted alkyl group, or a substituted or unsubstituted condensed ring aromatic group, and non-limiting examples thereof include the structure,

[0037] The carbon atom marked with * is an R configuration, an S configuration, or an achiral carbon atom.

[0038] The fifth aspect of the present invention provides a synthesis process of a prostaglandin intermediate represented by formula V, comprising a compound of formula IV:

[0039] Under an inert atmosphere, compound IV and imidazole are dissolved in an organic solvent, and tert-butyldiphenylsilyl chloride is added to obtain a compound of formula V;

[0040]

[0041] The R1 is selected from substituted or unsubstituted alkyl, and any H on the R1 is substituted by an aryl group;

[0042] The carbon atom marked with * is an R configuration, an S configuration, or an achiral carbon atom.

[0043] The sixth aspect of the present invention provides a synthesis process of a prostaglandin intermediate represented by formula IV, comprising a compound of formula III:

[0044] Under an inert atmosphere, the compound of formula III is dissolved in an organic solvent, and tri-n-butyltin hydride and azobisisobutyronitrile are added to obtain a compound of formula IV;

[0045]

[0046] The R is selected from -SR a , the R a is selected from substituted or unsubstituted alkyl;

[0047] The R1 is selected from substituted or unsubstituted alkyl, and any H on the R1 is substituted by an aryl group;

[0048] The carbon atom marked with * is an R configuration, an S configuration, or an achiral carbon atom.

[0049] The seventh aspect of the present invention provides a synthesis process of a prostaglandin intermediate represented by formula III, comprising:

[0050] Compound of formula II The compound of formula II is mixed in an organic solvent, and then an additive, N,N-diisopropylethylamine and crotonaldehyde are added to undergo a condensation reaction to obtain a compound of formula III;

[0051]

[0052] The additive is selected from one of titanium tetrachloride and dibutyl boron trifluoromethanesulfonate;

[0053] When the additive is selected from titanium tetrachloride, N-methylpyrrolidone is also added to the organic solvent;

[0054] The R is selected from -SR a , the R a is selected from substituted or unsubstituted alkyl;

[0055] The R1 is selected from substituted or unsubstituted alkyl, and any H on the R1 is substituted by an aryl group;

[0056] The carbon atom marked with * is an R configuration, an S configuration, or an achiral carbon atom.

[0057] In some specific embodiments of the synthesis process of the prostaglandin intermediate proposed in the seventh aspect,

[0058] Compound I is added into the reaction system to react to obtain a compound of formula II;

[0059]

[0060] The reaction system comprises an organic solvent, a 2-oxazolidinone derivative, 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride, 4-dimethylaminopyridine, and N,N-diisopropylethylamine.

[0061] or,

[0062] The reaction system comprises an organic solvent and N,N'-carbonyldiimidazole;

[0063] The R is selected from -SR a , the R a Selected from substituted or unsubstituted C1-C6 alkyl;

[0064] The R1 is selected from substituted or unsubstituted C1-C4 alkyl, and any H on the R1 is substituted by an aryl group or an alkyl group;

[0065] The carbon atom marked with * is an R configuration, an S configuration, or an achiral carbon atom.

[0066] In some specific embodiments of the synthesis process of the prostaglandin intermediate proposed in the seventh aspect,

[0067] Compound Ic, n-butyl lithium and (R)-4-benzyl-2-oxazolidinone are dissolved in an organic solvent to obtain compound II-c, such as:

[0068]

[0069] The eighth aspect of the present invention is a process for synthesizing a prostaglandin intermediate represented by formula X, comprising:

[0070] The compound of formula IX, In an inert atmosphere, the compound of formula IX is dissolved in an organic solvent, and a catalyst is added to react to obtain a product of formula X, such as:

[0071]

[0072] Said R2 is selected from a hydroxyl protecting group;

[0073] The hydroxy protecting group is optionally a silicon protecting group, such as any of trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, diphenylmethylsilyl, diphenyltert-butylsilyl, or 2-tetrahydropyranyl;

[0074] The catalyst [Rh((Sc, Rp)-DuanPhos)(COD)]SbF6 is prepared by mixing a metal precursor with an additive to form a mixed system, and a ligand is added to the mixed system to obtain the catalyst. The ligand structure is as follows:

[0075]

[0076] The metal precursor is [Rh(COD)Cl]2;

[0077] The additive is AgSbF6;

[0078] The organic solvent is selected from dichloromethane, 1,2-dichloroethane, chloroform and chlorobenzene. When dichloromethane, 1,2-dichloroethane, chloroform and chlorobenzene are used as the solvent in Example 9 of the present invention, the yields are 91%, 95%, 92% and 86% respectively.

[0079] The reagents used in the present invention are purchased from the open legal market and are not further purified.

[0080] In the embodiment of the present invention: The structure is selected from one of VI-a, VI-b, VI-c, and VI-d;

[0081]

[0082] In the present invention, the room temperature is 5-40°C, in some embodiments, the room temperature is 10-35°C, in some embodiments, the room temperature is 15-30°C, in some embodiments, the room temperature is 20-25°C, in some embodiments, the room temperature is 25°C.

[0083] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon radical, the carbon ring 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, more preferably 3 to 6 carbon atoms. Wherein the partially unsaturated monocyclic or polycyclic hydrocarbon radical is a saturated cycloalkyl radical or may optionally contain one, two or more double bonds and / or triple bonds on its ring, thereby forming a so-called cycloalkenyl or cycloalkynyl radical.

[0084] Advantages of the present invention:

[0085] The present invention provides a novel synthesis of a prostaglandin chiral intermediate, such as (R, E)-3-((tert-butyldiphenylsilyl)oxy)-N-methoxy-N-methylhex-4-enamide. The process is simple to operate, has cheap raw materials, and mild reaction conditions, and is suitable for industrial production. In particular, the ligand (Sc, Rp)-Duanphos in the catalyst used in Example 9 has better activity than the (S)-BINAP ligand used in the prior art, significantly reduces the amount of Rh metal used, and reduces the production cost beyond expectations. The chiral auxiliary agent adds an ethylthio side arm to improve the chiral control selectivity of the aldol condensation reaction. The cheap and easily available (R)-4-benzyl-2-oxazolidinone Evans chiral auxiliary group is used to induce the formation of chirality, so that the process cost has certain advantages. It is estimated that the kilogram-level material cost of the intermediate product compound X is about 10,000 yuan / kg. BRIEF DESCRIPTION OF THE DRAWINGS

[0086] Figure 1 Shown is the NMR hydrogen spectrum of compound III-a. DETAILED DESCRIPTION

[0087] The following will be combined with the embodiments of the present invention and the accompanying drawings to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0088] The present invention provides a process for synthesizing a chiral intermediate of prostaglandins.

[0089] The process flow is as follows:

[0090]

[0091] The present invention adopts the following technical scheme: a synthesis process of a prostaglandin intermediate comprises the following steps:

[0092] In the first step, an acetic acid derivative undergoes a condensation reaction with a 2-oxazolidinone derivative to prepare compound II;

[0093] In the second step, compound II undergoes an aldol condensation reaction with crotonaldehyde to obtain compound III;

[0094] In the third step, compound III undergoes a free radical reaction to remove the side chain to obtain compound IV;

[0095] Step 4: Compound IV undergoes a substitution reaction with tert-butyldiphenylsilyl chloride to obtain compound V;

[0096] The fifth step is to hydrolyze compound V under alkaline conditions to form carboxylic acid, and then form a co-crystallization reaction with di(cyclohexyl)amine to obtain compound VI;

[0097] Step 6: Compound VI is dissociated under acidic conditions to remove di(cyclohexyl)amine to obtain compound VII;

[0098] In the seventh step, compound VII undergoes a condensation reaction with dimethylhydroxylamine hydrochloride to obtain compound VIII.

[0099] Example 1

[0100]

[0101] In the first step, after nitrogen purging the reactor (10 L) for 10 to 20 minutes, dichloromethane (1 L) was added into the reactor, (R)-4-benzyl-2-oxazolidinone (550.0 g), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (595.0 g) and 4-dimethylaminopyridine (37.92 g) were transferred to the reactor under nitrogen protection with dichloromethane (2.3 L); stirring was started and N,N-diisopropylethylamine (1350 mL) was added.

[0102] Under nitrogen protection, slowly add compound Ia (373.0 g) to the reaction system through a constant pressure dropping funnel; control the temperature to less than 30°C. After the addition of compound Ia, stir at room temperature for 10 hours. Then add materials, add 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (178.5 g), 4-dimethylaminopyridine (15.2 g) and compound Ia (93.0 g) to the reaction system, and stir at room temperature for 10 hours after the addition. After the reaction is completed, cool the reaction system to 0°C, add dilute hydrochloric acid aqueous solution (2M, 3L) to the reaction system, stir vigorously for 10 minutes, and separate the liquids. The organic phase is washed with dilute hydrochloric acid aqueous solution (2M, 1L) and saturated sodium bicarbonate aqueous solution (1L) in turn. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated. The residue was subjected to flash column chromatography (ethyl acetate: petroleum ether = 1:10). The organic phases were collected and the solvent was evaporated to obtain compound II-a (yield: 78.4%, purity: 98.40%).

[0103] 1 H NMR(400MHz,Chloroform-d)δ7.36–7.17(m,5H),4.67(ddt,J=9.3,7.7,3.2Hz,1H),4.24–4.12(m,2H),3.93–3.74 (m,2H),3.26(dd,J=13.5,3.4Hz,1H),2.80(dd,J=13.5,9.3Hz,1H),2.64(q,J=7.4Hz,2H),1.28(t,J=7.4Hz,3H).

[0104] 13 C NMR (101MHz, Chloroform-d) δ169.29,153.18,135.20,129.50,129.50,128.94,128.94,127.34,66.25,55.10,37.64,34.13,26.23,14.36.

[0105]

[0106] In the second step, after nitrogen purging the reactor (10L) for 10 to 20 minutes, nitrogen protection was passed throughout the reactor. Compound II-a (679g) was dissolved in dichloromethane (DCM, 4.2L) and transferred to the reactor. When the temperature in the reactor dropped to -20°C, titanium tetrachloride (484.1g) was added dropwise, and the temperature was controlled within -20°C.

[0107] After the titanium tetrachloride was added dropwise, the mixture was stirred for half an hour at a temperature maintained, and then N,N-diisopropylethylamine (471.2 g) was added dropwise, and the temperature was controlled between -20°C and -30°C.

[0108] After the addition of N,N-diisopropylethylamine, stir at room temperature for half an hour. Then, add N-methylpyrrolidone (241.0 g) dropwise, and control the temperature between -20°C and -30°C. After the addition of N-methylpyrrolidone, stir at room temperature for half an hour. Then, add crotonaldehyde (255.6 g) dropwise, and control the temperature within -30°C.

[0109] After the addition of crotonaldehyde, the reaction was kept warm for 1 hour. After the reaction was completed, the reaction system was heated to -20°C, and an aqueous solution of ammonium chloride (12wt%, 3L) was added to quench the reaction, and the temperature was raised to room temperature, and the mixture was stirred vigorously for 10 minutes, allowed to stand, and separated. The organic phase was washed with an aqueous solution of ammonium chloride (12wt%, 1L), and the organic phase was dried over anhydrous sodium sulfate, and the solvent was evaporated to obtain compound III-a (yield: 95.1%).

[0110] 1 H NMR(400MHz,Chloroform-d)δ7.40–7.25(m,5H),5.85(dtd,J=16.1,6.5,0.9Hz,1H),5.6 0–5.49(m,1H),4.85(d,J=8.1Hz,1H),4.73(ddt,J=9.3,7.2,3.6Hz,1H),4.47(t,J=7.6H z, 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 does not show a peak)

[0111]

[0112] The third step is to purge the reactor (10L) with nitrogen for 10 to 20 minutes, and then pass nitrogen protection throughout the reactor. Dissolve compound III-a (849.0g) in toluene (5.0L) and transfer it to the reaction. Pass nitrogen into the bottom of the reactor for bubbling, exclude the air in the solvent, and bubble for 1 hour. Add tri-n-butyltin hydride (848.6g) and azobisisobutyronitrile (79.8g), and bubble for another 10 minutes. Heat to 85°C and keep warm for 1.5 hours. After the reaction is completed, evaporate the solvent. Add n-heptane-1 (1L) to the residue, stir for 10 minutes, let stand for 20 minutes, and pour out the upper organic phase. Add n-heptane-2 (500mL) to the residue and repeat the above operation twice. Dissolve the residue with isopropanol (990mL) and transfer it to the reactor, and add n-heptane-3 (990mL) dropwise. The temperature was lowered to 0°C and seed crystal IV-a (5 g) was added, stirred until a large amount of solid precipitated, and n-heptane-3 (1.98 L) was continued to be added dropwise. After the addition was completed, the mixture was kept stirred at 0°C for 3 hours. The mixture was filtered under reduced pressure, and the filter cake was washed with a solvent (isopropanol: n-heptane = 1:6, 200 mL). The filter cake was vacuum dried to obtain a yellow solid compound IV-a (yield: 70.3%, purity: 96.76%).

[0113]

[0114] In the fourth step, the three-necked flask (2L) was purged with nitrogen. Under the protection of nitrogen, compound IV-a (105g), imidazole (29.7g) and solvent dichloromethane (1L) were added in sequence, and then the reaction system was cooled to 0°C. Tert-butyldiphenylchlorosilane (104.7g) was added dropwise, and the temperature was controlled within 10°C. After the addition of tert-butyldiphenylchlorosilane, the temperature was raised to room temperature and reacted for 2 hours. The reaction solution was filtered under reduced pressure on diatomaceous earth. The filter cake was washed with dichloromethane (50mL×3). The organic phase was washed with saturated aqueous ammonium chloride solution (100mL×2) and saturated aqueous sodium chloride solution (50mL) in sequence. The organic phase was dried over anhydrous sodium sulfate, filtered under reduced pressure, and the solvent was evaporated to obtain compound Va (yield: 95%).

[0115] 1H NMR(400MHz,Chloroform-d)δ7.84–7.75(m,4H),7.44(dt,J=8.5,6.3Hz,6H),7.40–7.20(m,5 H),5.56(ddd,J=15.3,7.7,1.8Hz,1H),5.41–5.27(m,1H),4.84(q,J=6.8Hz,1H),4.59(ddt,J =10.5,6.8,3.1Hz,1H),4.16–4.03(m,2H),3.40(dd,J=15.7,7.0Hz,1H),3.25(td,J=15.7,14 .5,7.9Hz,2H),2.70(dd,J=13.4,9.6Hz,1H),1.54(dd,J=6.5,1.6Hz,3H),1.17–1.11(m,9H).

[0116] 13 C NMR(101MHz,Chloroform-d)δ170.31,153.35,136.14,136.14,136.05,136.05,135.48,134.23,134.19,132.80,129.63,129.55,129.46,129 .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.

[0117]

[0118] In the fifth step, compound Va (235.0 g) was dissolved in tetrahydrofuran (1175 mL) and transferred to a three-necked reaction bottle (3 L), nitrogen was replaced, and the temperature was lowered to 0°C. A hydrogen peroxide solution (30% aq., 232.2 g) was added, followed by a solution of LiOH·H2O (29.9 g) in water (588 mL), while the temperature was controlled within 5°C. After the lithium hydroxide aqueous solution was added, the mixture was stirred and reacted for 2 hours. After the reaction was completed, the reaction system was cooled to 0°C, sodium bisulfite (40% aq., 100 mL) was added dropwise to quench, the temperature was controlled within 15°C, stirred for 30 minutes, and the hydrogen peroxide was tested with starch potassium iodide test paper to see if it was completely quenched. 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 separated. The aqueous phase was extracted with methyl tert-butyl ether (500 mL) and the organic phases were combined and dried over anhydrous sodium sulfate. Filtered and the filtrate was collected.

[0119] According to the conditions shown in Table 1, alkylamine (0.11 mol) was added to the filtrate for the first time, and then seed crystals (1 g) were added to precipitate a large amount of solids, and then alkylamine (0.33 mol) was added for the second time. After the addition, stirring was continued for 12 hours. The filter cake was filtered under reduced pressure and washed with a solvent (methyl tert-butyl ether: n-heptane = 1:5, 250 mL). The filter cake was vacuum dried, and group 1 to group 4 tests were made respectively, and the yield % and purity % of the product were obtained by testing.

[0120] Table 1:

[0121]

[0122] The sixth step reaction is as follows:

[0123]

[0124] In the sixth step, any one of compounds VI-a, VI-b, VI-c, and VI-d (207 g) is used as a substrate and dispersed with ethyl acetate (1.5 L), and an aqueous solution (800 mL) of concentrated sulfuric acid (36.9 g) is added dropwise, and the temperature is controlled below 25°C. After vigorous stirring for 1 hour, the solution becomes clear, and the liquid is separated after standing for 30 minutes. An aqueous solution (400 mL) of concentrated sulfuric acid (14.77 g) is added to the organic phase. After vigorous stirring for 30 minutes, standing, and liquid separation, the organic phase is washed with water (200 mL), saturated sodium bicarbonate aqueous solution (200 mL), and saturated brine (200 mL) in turn. The organic phase is dried over anhydrous sodium sulfate, filtered with diatomaceous earth, and the solvent is evaporated to make groups 5 to 8, and the product compound VII-a is obtained, and the yield % and purity % are measured, as shown in Table 2.

[0125] Table 2:

[0126] Substrate Yield (%) purity(%) Group 5 VI-a 97.2 97.49 Group 6 VI-b 94.5 95.35 Group 7 VI-c 93.3 94.27 Group 8 VI-d 92.1 92.80

[0127] The NMR data of VII-a are as follows:

[0128] 1 H NMR(400MHz,Chloroform-d)δ11.61(s,1H),7.75(ddq,J=8.1,3.2,1.6Hz,4H),7.52–7.39(m,6H),5.50(ddt,J=15.2,7.5,1.7Hz,1H) ,5.40–5.27(m,1H),4.63(q,J=6.6,6.1Hz,1H),2.73–2.62(m,1H),2.58–2.48(m,1H),1.55(dd,J=6.4,1.9Hz,3H),1.17–1.04(m,9H).

[0129] 13C NMR(101MHz,Chloroform-d)δ177.31,136.09,136.09,135.98,135.98,133.99,133.84,132.14,129.7 3,129.59,127.58,127.58,127.58,127.42,127.42,71.52,43.61,27.02,27.02,27.02,19.34,17.48.

[0130]

[0131] Step 7: Purge the reactor (2L) with nitrogen for 10 minutes, add N,N-dimethylpyridine (4.5g), dimethylhydroxylamine hydrochloride (44.5g) and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (87.4g), dissolve with dichloromethane (500mL), cool to 10°C, then drop N,N-diisopropylethylamine (137.5g), and control the temperature below 10°C. Dissolve compound VII-a (140.0g) with dichloromethane (200mL) and slowly drop it into the reaction system, and control the temperature below 10°C. After the addition of compound VII-a, heat to room temperature and stir to react for 16 hours. After the reaction is completed, add dichloromethane (400mL) and dilute hydrochloric acid (700mL, 2M) to the reaction solution, stir vigorously for 10 minutes, let stand, and separate. The organic phase was then washed with dilute hydrochloric acid (300 mL, 2M), saturated aqueous sodium bicarbonate solution (300 mL) and saturated brine (200 mL) in that order. The organic phase was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated to obtain compound VIII-a (yield: 96%, purity: 95%, chiral purity: 95%).

[0132] 1 H NMR(400MHz,Chloroform-d)δ7.72(tt,J=6.2,1.7Hz,4H),7.40(dtq,J=11.1,6.4,2.1Hz,6H),5.48(ddt,J=15.3,7.4,1.7Hz,1H),5.36–5.23(m,1H), 4.75(q,J=7.0Hz,1H),3.61(s,3H),3.14(s,3H),2.87(dd,J=14.8,7.0Hz,1 H), 2.53 (dd, J=14.5, 6.5Hz, 1H), 1.50 (dd, J=6.5, 1.6Hz, 3H), 1.09 (s, 9H).

[0133] 13C NMR(101MHz,Chloroform-d)δ171.66,136.04,136.04,136.00,136.00,134.35,134.16,133.00,129.54,129. 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.

[0134] Example 2: (Synthesis of Compound II-b)

[0135]

[0136] In the first step, (R)-4-benzyl-2-oxazolidinone (12.0g), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (19.47g) and 4-dimethylaminopyridine (827.3mg) were added to the reaction bottle, dissolved with dichloromethane (120mL), and nitrogen was replaced. N,N-diisopropylethylamine (21.9g) was added; compound Ia (8.63g) was added dropwise; the temperature was controlled to within 20°C. After the compound Ia was added dropwise, it was stirred at room temperature for 16 hours. After the reaction was completed, the reaction system was cooled to 0°C, and a dilute hydrochloric acid aqueous solution (2M, 60mL) was added to the reaction system. After vigorous stirring for 10 minutes, the liquid was separated, and the organic phase was washed with a dilute hydrochloric acid aqueous solution (2M, 50mL) and a saturated sodium bicarbonate aqueous solution (50mL) in turn. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated. The residue was subjected to flash column chromatography (ethyl acetate:petroleum ether=1:9), the eluent was collected, and the solvent was evaporated to obtain compound II-b (yield: 67%, purity: 98.23%).

[0137] Example 3: (Synthesis of Compound II-c)

[0138]

[0139] In the first step, compound Ic, (R)-4-benzyl-2-oxazolidinone (35.0 g) was added to the reaction flask, solvent dichloromethane (350 mL) was added, the temperature was lowered to -60 ° C, n-butyl lithium (2.4 M, 99 mL) was added dropwise, the temperature was controlled below -60 ° C, and the mixture was stirred for half an hour. Chloroacetyl chloride (24.5 g) was added dropwise, the temperature was controlled below -50 ° C, and the mixture was kept at -50 ° C for 1 hour. After the reaction was completed, the reaction was quenched with saturated aqueous ammonium chloride solution (150 mL), and the organic phase was washed with saturated aqueous ammonium chloride solution (150 mL), saturated aqueous sodium bicarbonate solution (100 mL) and saturated brine (50 mL) in sequence. 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), the eluent was collected, and the solvent was evaporated to obtain compound II-c (yield: 85%, purity: 96.35%)

[0140] Example 4: (Synthesis of Compound II-d)

[0141]

[0142] In the first step, (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 with dichloromethane (50 mL), and nitrogen was replaced. N,N-diisopropylethylamine (11.3 g) was added; compound Ia (5.5 g) was added dropwise; the temperature was controlled to less than 20°C. After the compound Ia was added dropwise, it was stirred at room temperature for 16 hours. After the reaction was completed, the reaction system was cooled to 0°C, and a dilute hydrochloric acid aqueous solution (2M, 25 mL) was added to the reaction system. After vigorous stirring for 10 minutes, the liquid was separated, and the organic phase was washed with a dilute hydrochloric acid aqueous solution (2M, 20 mL) and a saturated sodium bicarbonate aqueous solution (20 mL) in turn. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated. The residue was subjected to flash column chromatography (ethyl acetate: petroleum ether = 1:9), the eluent was collected, and the solvent was evaporated to obtain compound II-d (yield: 83%, purity: 97.23%)

[0143] Example 5: (Second Synthesis Method of Compound II-a)

[0144]

[0145] Compound Ia (44.1 g) was added to the reaction flask, solvent dichloromethane (500 mL) was added, the temperature was lowered to 0°C, N, N'-carbonyldiimidazole (67.8 g) was added, and the reaction was kept warm for 2 hours. (R)-4-benzyl-2-oxazolidinone (50.0 g) was added, the mixture was stirred for half an hour, and the temperature was raised to room temperature for 12 hours. After the reaction was completed, the reaction system was cooled to 0°C, and a dilute hydrochloric acid aqueous solution (2M, 200 mL) was added to the reaction system. After vigorous stirring for 10 minutes, the liquid was separated, and the organic phase was washed with a dilute hydrochloric acid aqueous solution (2M, 200 mL) and a saturated sodium bicarbonate aqueous solution (100 mL) in turn. 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, the solvent was evaporated, and compound II-a (yield: 76%, purity: 97.37%) was obtained.

[0146] Example 6: (Second Synthesis Method of Compound III-a)

[0147]

[0148] In the second step, compound II-a (10.0 g) was added to the reaction bottle, solvent dichloromethane (150 mL) was added, nitrogen was replaced, and the temperature was lowered to -40 ° C. Dibutylborane trifluoromethanesulfonate (1M, 43.2 mL) was added dropwise, the temperature was controlled below -40 ° C, and the mixture was stirred for half an hour. N, N-diisopropylethylamine (44.6 g) was added dropwise, the temperature was controlled below -40 ° C, and the mixture was stirred for half an hour. The temperature was lowered to -78 ° C, crotonaldehyde (3.8 g) was added dropwise, and the temperature was controlled below -70 ° C. The mixture was stirred for half an hour, the temperature was raised to -40 ° C, and the reaction was stirred 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%, 60 mL) was added to quench the reaction, the temperature was raised to room temperature, the mixture was stirred vigorously for 10 minutes, the mixture was allowed to stand, and the mixture was separated. The organic phase was washed with aqueous ammonium chloride solution (12wt%, 60mL), saturated sodium bicarbonate solution (10mL) and saturated brine (10mL) in sequence. 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, and the solvent was evaporated to obtain compound III-a (yield: 84%, purity: 99.17%).

[0149] Example 7: (Second Synthesis Method of Compound VIII-a)

[0150]

[0151] Compound VII-a (50.0 g) was added to the reaction flask, solvent dichloromethane (500 mL) was added, the temperature was lowered to 0 ° C, N, N'-carbonyldiimidazole (26.2 g) and triethylamine (24.7 g) were added, and the reaction was kept warm for 2 hours. Dimethylhydroxylamine hydrochloride (15.9 g) was added, the mixture was stirred for half an hour, and the temperature was raised to room temperature for 12 hours. After the reaction was completed, the reaction system was cooled to 0 ° C, and a dilute hydrochloric acid aqueous solution (2M, 200 mL) was added to the reaction system. After vigorous stirring for 10 minutes, the liquid was separated, and the organic phase was washed with a dilute hydrochloric acid aqueous solution (2M, 200 mL) and a saturated sodium bicarbonate aqueous solution (100 mL) in turn. 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 VIII-a (yield: 84%, purity: 98.16%).

[0152] Example 8

[0153]

[0154] After nitrogen purging the 20L reactor for 10 to 20 minutes, the temperature was lowered, 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 slight nitrogen purging protection; stirring was started, and the temperature was lowered to -25 to -30 ° C under slight nitrogen flow protection; n-butyl lithium n-hexane solution (2.5 M, 1.1 L) was dripped into the system through a constant pressure dropping funnel under slight nitrogen flow; after the addition was completed, the system was kept warm and stirred for 1 hour at below -20 ° C. The temperature in 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 dripped into the reactor. After the addition was completed, 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 (1.2M, 3.36L) was added to the reaction system at once, and after vigorous stirring for 5 minutes, the mixture was allowed to stand for separation. The lower aqueous phase was discharged, and the organic phase was washed with a saturated sodium bicarbonate aqueous solution (2.2L) again. After stirring for 5 minutes, the mixture was allowed to stand for separation. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure at 40°C. The residue was dissolved with n-heptane (2.5L), cooled to 0°C, stirred overnight, filtered, and the filtrate was collected. The filtrate was cooled to -20°C, and seed crystals of compound IX (5g) were added, stirred overnight, filtered at low temperature, and the filter cake was washed with cooled n-heptane (-20°C), and vacuum dried at room temperature to obtain compound IX (yield: 90%, purity: 98.64%, chiral purity: 97.10%).

[0155] Example 9

[0156]

[0157] Catalyst configuration steps:

[0158] Weigh the metal precursor (1,5-cyclooctadiene) rhodium chloride (I) dimer (100 mg) and silver hexafluoroantimonate (139 mg), add ultra-dry acetone (20 mL) to dissolve, replace nitrogen three times and stir at room temperature for half an hour. Under nitrogen environment, filter out the solid in the solution, add ligand (Sc, Rp)-DuanPhos (160 mg), replace nitrogen three times and stir at room temperature for half an hour, then use an oil pump to dry the solvent, and store the prepared catalyst [Rh((Sc, Rp)-DuanPhos)(COD)]SbF6 in a glove box.

[0159] Preparation steps of compound X:

[0160] Weigh compound IX (200.0 g) and the prepared catalyst [Rh((Sc, Rp)-DuanPhos)(COD)]SbF6 (160 mg, 0.005 eq.) in a 5 L round-bottom flask, add distilled solvent 1,2-dichloroethane (2.0 L), replace nitrogen three times and heat to 60 ° C for 3 hours. After the reaction is completed, the reaction solvent is concentrated to remove, 2.0 L of n-heptane is added to dilute the crude product, and column chromatography (petroleum ether: ethyl acetate = 20:1) is performed, and the eluent is collected and concentrated under reduced pressure at 40 ° C to obtain compound X (yield: 95%, purity: 98.32%).

[0161] Comparative Example 1

[0162] The ligand type and metal precursor in the catalyst configuration step in Example 9, and the solvent type in the compound X preparation step were replaced with the conditions shown in Table 3 to make groups 1 to 15. The results are shown in Table 3:

[0163] Table 3

[0164] Ligand Solvents Metal Precursors Yield % Group 1 (S)-MeO-Biphep / / 24％ Group 2 (Sc,Rp)-TangPhos / / 41％ Group 3 (Sc,Rp)-ZhangPhos / / 35％ Group 4 (S)-Segphos / / 15％ Group 5 (S)-BINAP / / 14％ Group 6 / Tetrahydrofuran / 23％ Group 7 / N,N-Dimethylformamide / 0％ Group 8 / Toluene / 35％ Group 9 / Acetonitrile / 0％ Group 10 / 1,4-Dioxane / 10％ Group 11 / / <![CDATA[Rh(NBD)2SbF6]]> 32％ Group 12 / / <![CDATA[RhCl(PPh3)3]]> 8％ Group 13 / / <![CDATA[Rh(NBD)2BF4]]> Trace Group 14 / / <![CDATA[Rh(COD)2PF6]]> Trace

[0165] In Table 3, “ / ” indicates the same as in Implementation 9;

[0166] It will be apparent to those skilled in the art that the 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 the spirit or essential features of the invention. Therefore, the embodiments should be considered exemplary and non-limiting in all respects, and the scope of the invention is defined by the appended claims rather than the foregoing description, and it is intended that all variations falling within the meaning and scope of the equivalent elements of the claims be included in the invention. Any reference numeral in a claim should not be considered as limiting the claim to which it relates.

[0167] In addition, it should be understood that although the present specification is described according to implementation modes, not every implementation mode contains only one independent technical solution. This description of the specification is only for the sake of clarity. Those skilled in the art should regard the specification as a whole. The technical solutions in each embodiment may also be appropriately combined to form other implementation modes that can be understood by those skilled in the art.

Claims

1. A prostaglandin intermediate, such as formula A: The R1 is selected from substituted or unsubstituted tert-butyl, substituted or unsubstituted benzyl; The R3 is selected from The R is selected from H or -SR a , the R a Selected from substituted or unsubstituted C1-C6 alkyl; The carbon atom marked with * is an R configuration, an S configuration, or an achiral carbon atom.

2. A process for synthesizing a prostaglandin intermediate of formula VIII, comprising a compound of formula VII: Adding compound VII to the reaction system to obtain a compound of formula VIII; The reaction system is prepared 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 comprises N,N'-carbonyldiimidazole, organic amine hydrochloride, triethylamine and an organic solvent; Said R2 is selected from a hydroxyl protecting group; The carbon atom marked with * is an R configuration, an S configuration, or an achiral carbon atom.

3. A synthesis process of a prostaglandin intermediate represented by formula VII, comprising a compound of formula VI: The compound of formula VI is mixed with an acid to dissociate to obtain a compound of formula VII; Said R2 is selected from a hydroxyl protecting group; The R4 and R5 are each independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl; The carbon atom marked with * is an R configuration, an S configuration, or an achiral carbon atom.

4. A process for synthesizing a prostaglandin intermediate of formula VI, comprising: a compound of formula V Hydrogen peroxide is added to an organic solution of the compound of formula V, followed by dropwise addition of an aqueous lithium hydroxide solution, followed by extraction with an organic solvent, and the compound of formula V-1 is added to the extracted organic phase to obtain a compound of formula VI; The R1 is selected from substituted or unsubstituted alkyl, and any H on the R1 is substituted by an aryl group; Said R2 is selected from a hydroxyl protecting group; The R4 and R5 are each independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl; The carbon atom marked with * is an R configuration, an S configuration, or an achiral carbon atom.

5. A process for synthesizing 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-butyldiphenylsilyl chloride is added to obtain a compound of formula V; The R1 is selected from substituted or unsubstituted alkyl, and any H on the R1 is substituted by an aryl group; The carbon atom marked with * is an R configuration, an S configuration, or an achiral carbon atom.

6. A process for synthesizing a prostaglandin intermediate of formula IV, comprising a compound of formula III: Under an inert atmosphere, the compound of formula III is dissolved in an organic solvent, and tri-n-butyltin hydride and azobisisobutyronitrile are added to obtain a compound of formula IV; The R is selected from -SR a , the R a is selected from substituted or unsubstituted alkyl; The R1 is selected from substituted or unsubstituted alkyl, and any H on the R1 is substituted by an aryl group; The carbon atom marked with * is an R configuration, an S configuration, or an achiral carbon atom.

7. 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 an additive, N,N-diisopropylethylamine and crotonaldehyde are added to undergo a condensation reaction to obtain a 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 is selected from substituted or unsubstituted alkyl; The R1 is selected from substituted or unsubstituted alkyl, and any H on the R1 is substituted by an aryl group; The carbon atom marked with * is an R configuration, an S configuration, or an achiral carbon atom.

8. The process for synthesizing the prostaglandin intermediate according to claim 7, characterized in that: Compound I is added into the reaction system to react to obtain a compound of formula 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 comprises 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; The R1 is selected from substituted or unsubstituted C1-C4 alkyl, and any H on the R1 is substituted by an aryl group or an alkyl group; The carbon atom marked with * is an R configuration, an S configuration, or an achiral carbon atom.

9. The process for synthesizing the prostaglandin intermediate according to claim 7, characterized in that: Compound Ic, n-butyl lithium and (R)-4-benzyl-2-oxazolidinone are dissolved in an organic solvent to obtain compound II-c, such as:

10. A process for synthesizing a prostaglandin intermediate of formula X, comprising a compound of formula IX, In an inert atmosphere, the compound of formula IX is dissolved in an organic solvent, and a catalyst is added to react to obtain a product of formula X, such as: Said R2 is selected from a hydroxyl protecting group; The catalyst [Rh((Sc, Rp)-DuanPhos)(COD)]SbF6 is prepared by mixing a metal precursor with an additive to form a mixed system, and adding a ligand to the mixed system to obtain the catalyst. The ligand structure is as follows: The metal precursor is [Rh(COD)Cl]2; The additive is AgSbF6.

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