Triprostinil intermediate derivative and synthesis method thereof

Abstract

The invention relates to the field of drug intermediates, and particularly discloses a treprostinil intermediate derivative and a synthesis method thereof.The treprostinil intermediate derivative comprises intermediates shown in a formula I, a formula II and a formula III, the compound shown in the formula I is subjected to high-selectivity obtaining of the intermediate shown in the formula II under the action of a catalyst obtained through complexing of ligands (Sc, Rp)-Duanphos and a precursor, and the compound shown in the formula III is subjected to high-selectivity obtaining of the intermediate shown in the formula III. An intermediate shown in a formula III is obtained from the formula II under the action of a catalyst and a reducing agent, the intermediate shown in the formula III, such as a IIIa compound, is used for synthesizing an IVa compound, and the purpose of the invention is to develop a more practical method which involves fewer steps and chromatographic purification and synthesis of a key chiral intermediate through asymmetric hydrogenation. A chiral five-membered ring is selectively synthesized through a zhang-eneyne ring isomerization high diastereomer, so that the method is more suitable for enlarging the scale, the treprostinil intermediate is prepared, and a new treprostinil synthesis mode is developed by combining with the prior art.

Description

Technical Field

[0001] The invention relates to the technical field of pharmaceutical intermediates, and in particular to a treprostinil intermediate derivative and a synthesis method thereof. Background of the Invention

[0003] Treprostinil is a drug produced by United Therapeutics and approved by the U.S. Food and Drug Administration (FDA) for the treatment of pulmonary arterial hypertension.

[0004] Treprostinil is a synthetic analog of prostacyclin (PGI2) indicated for the treatment of pulmonary arterial hypertension (PAH). The main pharmacological mechanism of action of treprostinil is direct vasodilation of the pulmonary and systemic arterial vascular beds and inhibition of platelet aggregation.

[0005] US6700025 discloses a method for stereoselective synthesis of prostaglandin derivatives, in particular treprostinil, however this method and other known methods involve a large number of synthesis steps and chromatographic purification. The object of the present invention is to find a more practical method involving fewer steps and chromatographic purification, as well as highly diastereoselective resolution of key intermediates by enzymatic means, which makes the method more suitable for scale-up.

[0006] In 1985, Aristoff et al. first reported the synthesis of the tricyclic treprostinil, which was constructed through the key intramolecular Horner-Wadsworth-Emmons reaction, but did not involve chiral construction. In 2004, Moriarty et al. reported the construction of the key tricyclic intermediate of treprostinil through the Pauson-Khand reaction. Javier's research group used the same strategy to construct it through continuous flow synthesis. CN101891596B proposed the following path:

[0007]

[0008] The above synthesis methods involve several chiral intermediates, a large number of synthesis steps, separation of diastereomers and chromatographic purification, the steps are cumbersome, and there is material loss during the purification process, which increases the cost of the synthesis. Summary of the invention

[0009] In view of the problems existing in the prior art, the first aspect of the present invention provides a treprostinil intermediate derivative, such as Formula I:

[0010]

[0011] The carbon atom marked with * is an R configuration, an S configuration, or an achiral carbon atom;

[0012] The R 1 Selected from H, a hydroxyl protecting group;

[0013] The R 2 is selected from substituted or unsubstituted alkyl;

[0014] The R 3 and R 4 are each independently selected from hydrogen, substituted or unsubstituted alkyl,

[0015] or,

[0016] The R 3 and R 4 Together with the atoms to which they are attached, they form the ring Ar,

[0017] The ring Ar is selected from substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl;

[0018] The hydroxy protecting group is a silicon protecting group, such as any one of trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, diphenylmethylsilyl, diphenyltert-butylsilyl, or 2-tetrahydropyranyl.

[0019] The second aspect of the present invention provides a treprostinil intermediate derivative, such as the formula:

[0020]

[0021] It is stated represents a single or double bond;

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

[0023] The R 1 Selected from H, a hydroxyl protecting group;

[0024] The R 2 is selected from substituted or unsubstituted alkyl;

[0025] The R 3 and R 4 are each independently selected from hydrogen, substituted or unsubstituted alkyl,

[0026] or,

[0027] The R 3 and R 4 Together with the atoms to which they are attached, they form the ring Ar,

[0028] The ring Ar is selected from substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl;

[0029] The hydroxy protecting group is a silicon protecting group, such as any one of trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, diphenylmethylsilyl, diphenyltert-butylsilyl, or 2-tetrahydropyranyl.

[0030] The third aspect of the present invention provides a specific form of the Treprostinil intermediate derivative of the first aspect and the second aspect, as follows:

[0031]

[0032] The fourth aspect of the present invention provides a method for synthesizing the intermediate represented by formula I, comprising:

[0033] Under an inert atmosphere, compound B is dissolved in an organic solvent, a lithium reagent is added to obtain a reaction mixture, and a substrate of formula V is added to the reaction mixture to react to obtain a compound of formula I, such as:

[0034]

[0035] The lithium reagent is selected from one or a combination of n-butyl lithium, isobutyl lithium, tert-butyl lithium, methyl lithium, phenyl lithium, diisopropyl lithium amide, and 2,2,6,6-tetramethylpiperidinium lithium;

[0036] The carbon atom marked with * is an R configuration, an S configuration, or an achiral carbon atom;

[0037] The R 1 Selected from H, a hydroxyl protecting group;

[0038] The R 2 is selected from substituted or unsubstituted alkyl;

[0039] The R 3 and R 4 are each independently selected from hydrogen, substituted or unsubstituted alkyl,

[0040] or,

[0041] The R 3 and R 4 Together with the atoms to which they are attached, they form the ring Ar,

[0042] The ring Ar is selected from substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl;

[0043] The hydroxy protecting group is a silicon protecting group, such as any one of trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, diphenylmethylsilyl, diphenyltert-butylsilyl, or 2-tetrahydropyranyl.

[0044] The fifth aspect of the present invention provides a method for synthesizing an intermediate of formula II, comprising:

[0045] In an inert atmosphere, the compound of formula I is dissolved in an organic solvent, a catalyst is added, and the reaction is performed to obtain a product of formula II, such as:

[0046]

[0047] The carbon atom marked with * is an R configuration, an S configuration, or an achiral carbon atom;

[0048] The R 1 Selected from H, a hydroxyl protecting group;

[0049] The R 2 is selected from substituted or unsubstituted alkyl;

[0050] The R 3 and R 4 are each independently selected from hydrogen, substituted or unsubstituted alkyl,

[0051] or,

[0052] The R 3 and R 4 Together with the atoms to which they are attached, they form ring Ar;

[0053] The ring Ar is selected from substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl;

[0054] The catalyst is obtained by adding a ligand, an additive and a metal precursor into an organic solvent. The ligand structure of the catalyst is as follows:

[0055]

[0056] The metal precursor is selected from one of [Rh(COD)Cl]2, [Rh(ethylene)Cl]2, and [Rh(NBD)Cl]2;

[0057] The additive is selected from AgSbF6, AgOTf or AgBF4;

[0058] The hydroxy protecting group is a silicon protecting group, such as any one of trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, diphenylmethylsilyl, diphenyltert-butylsilyl, or 2-tetrahydropyranyl.

[0059] In some specific embodiments of the fifth aspect, the inert atmosphere is selected from one of nitrogen or argon or a mixture thereof.

[0060] In some specific embodiments of the fifth aspect, 0.20 to 0.25 mol of the compound of formula I is added into every 1 L of organic solvent.

[0061] In some specific embodiments of the fifth aspect, 0.008 to 0.012 mol of catalyst is added to every 1 L of organic solvent.

[0062] In some specific embodiments of the fifth aspect, the reaction temperature is 45-55°C.

[0063] The sixth aspect of the present invention provides a method for synthesizing an intermediate of formula III, comprising:

[0064] The compound of formula II is added into a reaction system consisting of a catalyst, a reducing agent and an organic solvent to obtain a compound of formula III;

[0065]

[0066] The R 1 Selected from H, a hydroxyl protecting group;

[0067] The R 2 is selected from substituted or unsubstituted alkyl;

[0068] The R 3 and R 4 are each independently selected from hydrogen, substituted or unsubstituted alkyl, or,

[0069] The R 3 and R 4 Together with the atoms to which they are attached, they form the ring Ar,

[0070] The ring Ar is selected from substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl;

[0071] The carbon atom marked with * is an R configuration, an S configuration, or an achiral carbon atom;

[0072] The hydroxy protecting group is a silicon protecting group, such as any one of trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, diphenylmethylsilyl, diphenyltert-butylsilyl, or 2-tetrahydropyranyl.

[0073] In some specific embodiments of the sixth aspect, the catalyst is selected from one or a combination of cuprous chloride, cuprous bromide or cuprous iodide.

[0074] In some specific embodiments of the sixth aspect, the organic solvent is selected from one or a combination of toluene, chlorobenzene, tetrahydrofuran, and hexamethylphosphamide.

[0075] In some specific embodiments of the sixth aspect, the reducing agent is selected from one or a combination of diisobutylaluminum hydride, red aluminum, trimethylsilane or triphenylsilane.

[0076] In some specific embodiments of the sixth aspect, the organic solvent comprises THF and HMPA, the volume ratio of THF and HMPA is (2-3):1, and / or the feed ratio of the reducing agent to the catalyst is (1.5-2.5):2.

[0077] In some specific embodiments of the sixth aspect, the feed ratio of the compound II to the catalyst is 1:(1.8-2.3).

[0078] The seventh aspect of the present invention provides a method for synthesizing a treprostinil intermediate represented by formula IV, comprising:

[0079] Dissolving compound III of formula III in an organic solvent, then adding Hoveyda-Grubbs catalyst and compound C, reacting to obtain compound IV of formula;

[0080]

[0081] The carbon atom marked with * is an R configuration, an S configuration, or an achiral carbon atom;

[0082] The R 1 Selected from H, a hydroxyl protecting group;

[0083] The R 2 is selected from substituted or unsubstituted alkyl;

[0084] The hydroxy protecting group is a silicon protecting group, such as any one of trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, diphenylmethylsilyl, diphenyltert-butylsilyl, or 2-tetrahydropyranyl.

[0085] The eighth aspect of the present invention provides a method for synthesizing a treprostinil intermediate shown in Formula 1, comprising:

[0086] Compound S1 is put into an organic solvent, a catalyst and KOMe are added, and the reaction is carried out under a hydrogen atmosphere to obtain a compound of formula 1;

[0087]

[0088] The R 1 Selected from H or a hydroxyl protecting group;

[0089] The R 2 is selected from substituted or unsubstituted alkyl;

[0090] The R 3 and R 4 are each independently selected from hydrogen, substituted or unsubstituted alkyl,

[0091] or,

[0092] The R 3 and R 4 Together with the atoms to which they are attached, they form the ring Ar,

[0093] The ring Ar is selected from substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl;

[0094] The carbon atom marked with * is an R configuration, an S configuration, or an achiral carbon atom;

[0095] The hydroxy protecting group is a silicon protecting group, such as any one of trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, diphenylmethylsilyl, diphenyltert-butylsilyl, or 2-tetrahydropyranyl.

[0096] The catalyst is obtained by complexing a ligand with a metal precursor. The ligand structure of the catalyst is as follows:

[0097]

[0098] The metal precursor is [Ir(COD)Cl]2;

[0099] In the present invention, DIBAL-H represents diisobutylaluminum hydride.

[0100] The reagents used in the present invention are purchased from the open legal market and are not further purified.

[0101] 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.

[0102] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon group, the carbocyclic 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. Where the partially unsaturated monocyclic or polycyclic cyclic hydrocarbon group is a saturated cycloalkyl group, it may optionally contain one, two or more double bonds and / or triple bonds on its ring, thereby forming a so-called cycloalkenyl or cycloalkynyl group.

[0103] Advantages of the present invention:

[0104] The purpose of the present invention is to develop a more practical method, which involves fewer steps and chromatographic purification, synthesizes key chiral intermediates by asymmetric hydrogenation, and synthesizes chiral five-membered rings by zhang-enyne ring isomerization with high diastereoselectivity, so that the method is more suitable for scale-up, prepares treprostinil and treprostinil intermediates, and develops a new treprostinil process synthesis route in combination with existing technologies. BRIEF DESCRIPTION OF THE DRAWINGS

[0105] Figure 1 1a shows the hydrogen spectrum NMR data of compound Ia;

[0106] Figure 2 : shows the carbon NMR data of compound Ia;

[0107] Figure 3 : shows the hydrogen spectrum NMR data of compound IIa;

[0108] Figure 4 : shows the carbon spectrum NMR data of compound IIa;

[0109] Figure 5 : shows the hydrogen spectrum NMR data of compound IIIa;

[0110] Figure 6 : shows the carbon spectrum NMR data of compound IIIa;

[0111] Figure 7 : shows the hydrogen spectrum NMR data of compound IV;

[0112] Figure 8 The carbon NMR data of compound IV are shown. DETAILED DESCRIPTION

[0113] The following will be combined with the drawings in the embodiments of the present application to clearly and completely describe the technical solutions in the embodiments of the present application. Obviously, the described embodiments are only part of the embodiments of the present application, not all of the embodiments. Based on the embodiments in the present application, all other embodiments obtained by ordinary technicians in this field based on the present application belong to the scope of protection of the present application.

[0114] Example 1 Synthesis of Compound S2

[0115]

[0116] Under nitrogen atmosphere, compound N-methoxy-N-methylacetamide (160mmol) was dissolved in anhydrous tetrahydrofuran (270mL), the reaction solution was cooled to -78°C, 2.0M lithium diisopropylamide tetrahydrofuran solution (79.8mL, 160mmol) was added dropwise, and the reaction was kept warm for 30 minutes. Then a solution of substrate compound S2b (53.2mmol) in tetrahydrofuran (20ml) was added dropwise. After 30 minutes of reaction, 10% ammonium chloride solution (100mL) was added to quench. Warm to room temperature and stand for separation, ethyl acetate (50ml) was added to the aqueous phase for extraction, the organic phases were combined, saturated brine (100ml) was added for washing, the organic phase was concentrated to dryness, and the column separation obtained compound S2 (yield 58%), which was directly used for the next step reaction. HRMS (ESI) Calcd for C9H 16 NO3[M+H] + 186.1125,found:186.1154.

[0117] Example 2 Synthesis of Compound S3

[0118]

[0119] The substrate compound S2b in Example 1 was changed to S3c to obtain compound S3 (yield 47.5%). Compound S3 was subjected to high-resolution mass spectrometry test to obtain HRMS (ESI) Calcd for C 10 H 18 NO3[M+H] + 200.1281,found:200.1297.

[0120] Example 3 Synthesis of Compound S4

[0121]

[0122] The substrate compound S2b in Example 1 was changed to S4d to obtain compound S4 (yield 51.2%). Compound S4 was subjected to high-resolution mass spectrometry test to obtain HRMS (ESI) Calcd for C 11 H 20 NO3[M+H] + 214.1438,found:214.1449.

[0123] Example 4 Synthesis of Compound S5

[0124]

[0125] The substrate compound S2b in Example 1 was changed to S5e to obtain compound S5 (yield 43.9%). Compound S5 was subjected to high-resolution mass spectrometry test to obtain HRMS (ESI) Calcd for C 10 H 18 NO3[M+H] + 200.1281,found:200.1295.

[0126] Example 5 Synthesis of Compound S6

[0127]

[0128] The substrate compound S2b in Example 1 was changed to S6f to obtain compound S6 (yield 46.9%). Compound S6 was subjected to high-resolution mass spectrometry test to obtain HRMS (ESI) Calcd for C 10 H 16 NO3[M+H] + 198.1125,found:198.1149.

[0129] Example 7 Synthesis of Compound 1

[0130]

[0131] In a glove box filled with nitrogen / inert atmosphere, [Ir(COD)Cl]2 (5×10 -3 mmol), ligand L1 (10×10 -3 mmol) and anhydrous isopropanol (1.0 mL). The above mixture was stirred at room temperature (20-30° C.) for 2 hours and set aside. The catalyst concentration was (10 μmol / L).

[0132] The substrate compound S1 (1.0 mmol) was put into 10 mL of toluene, and then a freshly prepared catalyst solution (0.1 mL, 10 μmol / L) and KOMe (0.05 mmol) were added. The operation was completed in a glove box filled with argon. The reaction mixture was transferred to an autoclave, filled with 60 atm of hydrogen, and stirred at room temperature for 24 hours. After slowly releasing hydrogen, the reaction mixture was concentrated and filtered through a silica gel column to remove the metal complex. The solvent was removed under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (eluent PE: EA = 1: 1) to obtain compound 1 (0.73 mmol, 73.2%) as a colorless oil.

[0133] 1 HNMR(400MHz, CDCl3)δ5.77-5.68(m,1H),5.55-5.48(m,1H),4.56-4.42(m,1H),3.8 2(d,J=3.3Hz,1H),3.66(s,3H),3.17(s,3H),2.74-2.49(m,2H),1.69-1.67(m,3H). 13 CNMR(101MHz,CDCl3)δ173.5,132.3,127.1,68.9,61.4,38.5,31.9,17.8.HRMS(ESI)Calcd for C8H 15 NO3Na[M+Na] + :196.0944,found:196.0943.

[0134] [α] 25 D :+44.7(c=1.0,CHCl3).

[0135] Example 8 Synthesis of Compound 2

[0136]

[0137] The input substrate of Example 7 was replaced by compound S2 from compound S1 to obtain compound 2 with a yield of 67.5%. Compound 2 was subjected to high-resolution mass spectrometry test and HRMS (ESI-TOF) was obtained: Calcd for C9H 17 NO3Na[M+Na] + :210.2282,found 210.2297.

[0138] Example 9 Synthesis of Compound 3

[0139]

[0140] The input substrate of Example 7 was replaced by compound S3 from compound S1 to obtain compound 3 with a yield of 69.7%. Compound 3 was subjected to high-resolution mass spectrometry test and HRMS (ESI-TOF) was obtained: Calcd for C 10 H 19 NO3Na[M+Na] + :224.1257,found 224.1268.

[0141] Example 10 Synthesis of Compound 4

[0142]

[0143] The input substrate of Example 7 was replaced by compound S4 from compound S1 to obtain compound 4 with a yield of 64.1%. Compound 4 was subjected to high-resolution mass spectrometry test and obtained HRMS (ESI-TOF): Calcd for C 11 H 21 NO3Na[M+Na] + :238.1412, found 238.1427.

[0144] Example 11 Synthesis of Compound 5

[0145]

[0146] The input substrate of Example 7 was replaced by compound S5 from compound S1 to obtain compound 5 with a yield of 68.0%. Compound 5 was subjected to high-resolution mass spectrometry test and HRMS (ESI-TOF) was obtained: Calcd for C 10 H 19 NO3Na[M+Na] + :224.1257,found 224.1261.

[0147] Example 12 Synthesis of Compound 6

[0148]

[0149] The input substrate of Example 7 was replaced by compound S6 from compound S1 to obtain compound 6 with a yield of 62.7%. Compound 6 was subjected to high-resolution mass spectrometry test and HRMS (ESI-TOF) was obtained: Calcd for C 10 H 17 NO3Na[M+Na] + :222.1100,found222.1127.

[0150] Example 13 (Protecting the hydroxyl group of compound 1)

[0151]

[0152] In a dried flask, substrate compound 1 (10.0 mmol, 1.0 equivalent) was added, dissolved with dichloromethane (DCM, 30.0 mL), and the system was cooled to 0° C. Subsequently, imidazole (22.0 mmol, 2.2 equivalent) was added in one portion under nitrogen protection.

[0153] TBSCl (tert-butyldimethylsilyl chloride, 17 mmol, 1.7 equivalents) was added dropwise, the reaction mixture was warmed to room temperature and stirred for 4 hours, and then the reaction was quenched with saturated sodium bicarbonate (NaHCO3) solution, the mixture was diluted with dichloromethane (DCM, 30.0 mL), the aqueous phase was extracted with dichloromethane (30.0 mL×3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate (Na2SO4), and concentrated under reduced pressure, and the crude product was purified by column chromatography (petroleum ether / ethyl acetate=60 / 1 to 30 / 1) to give compound 1-a with a yield of 99.24%.

[0154] Example 14 (Protecting the hydroxyl groups of compounds 2 to 6)

[0155]

[0156] In a dried flask, one of the substrate compounds 2-7 (10.0 mmol, 1.0 equivalent) was added, dissolved with dichloromethane (DCM, 30.0 mL), and the system was cooled to 0° C. Subsequently, imidazole (22.0 mmol, 2.2 equivalent) was added in one portion under nitrogen protection.

[0157] TBSCl (tert-butyldimethylsilyl chloride, 17 mmol, 1.7 equivalents) was added dropwise, the reaction mixture was warmed to room temperature and stirred for 4 hours, and then the reaction was quenched with saturated sodium bicarbonate (NaHCO3) solution, the mixture was diluted with dichloromethane (DCM, 30.0 mL), the aqueous phase was extracted with dichloromethane (30.0 mL×3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate (Na2SO4), and concentrated under reduced pressure, and the resulting crude product was purified by column chromatography (petroleum ether / ethyl acetate=60 / 1 to 30 / 1) to give the corresponding product compounds 2-b, 3-c, 4-d, 5-e, 6-f, 7-g, respectively, as shown in Table 1:

[0158] Table 1 Hydroxyl protection of compounds 2 to 7

[0159]

[0160]

[0161] Example 15 Synthesis of Compound Ia

[0162]

[0163] Under nitrogen protection, compound B (12 mmol, 1.5 equivalents) was dissolved in anhydrous tetrahydrofuran (THF, 16 mL), and n-butyl lithium (7.5 mL, 1.6 M in hexane) was added dropwise via a syringe at -78 ° C. The mixture was gradually warmed to -20 ° C and stirred for 30 minutes, then warmed to room temperature and stirred for 10 minutes, and then the reaction flask was re-cooled to -20 ° C to obtain a reaction mixture.

[0164] The substrate compound 1-a (8.0 mmol, 1.0 equivalent) was dissolved in anhydrous THF (8.0 mL) and added dropwise to the reaction mixture via a syringe. The mixture was stirred at -20°C for 30 minutes, then warmed to 0°C and stirred for 1 hour.

[0165] After the reaction was completed, the reaction was quenched with saturated ammonium chloride (NH4Cl) aqueous solution (30 mL), and then the organic phase was extracted with ethyl acetate (3×30 mL). The combined organic layer was washed with saturated brine (Brine) and dried over anhydrous sodium sulfate (Na2SO4). After the solvent was removed under reduced pressure, the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate=100 / 1 to 60 / 1) to obtain compound Ia (yield 92.81%).

[0166] The NMR data of compound 1a are: 1H NMR (400MHz, CDCl3) δ7.46-7.38(m,4H),7.37-7.32(m,1H),7.30(t,J=7.9Hz ,1H),7.21-7.13(m,2H),7.11-7.06(m,1H),5.74-5.60(m,1H),5.54-5.43(m ,1H),5.07(s,2H),4.81-4.68(m,1H),2.91(dd,J=14.6,8.1Hz,1H),2.72(dd ,J=14.6,5.0Hz,1H),1.72-1.66(m,3H),0.87(s,9H),0.05(d,J=9.2Hz,6H);

[0167] 13 C NMR (100MHz, CDCl3) δ185.9,158.7,136.5,133.4,129.9,128.8,128.3,127.6,126.5,1 25.9,121.2,118.6,118.4,90.9,88.3,70.6,70.3,54.3,25.9,18.3,17.7,-4.0,-4.8;

[0168] HRMS(ESI-TOF):Calcd for C 27 H 34 NaO3Si + [M+Na] + :457.2169, found 457.2164; [α] 26 D=+0.4(c 0.93,CH2Cl2).

[0170] Example 16 Synthesis of Compound Ib

[0171]

[0172] The substrate in Example 15 was replaced by compound 2-b from compound 1-a to obtain compound Ib with a yield of 91.55%. Compound Ib was subjected to high-resolution mass spectrometry test and HRMS (ESI-TOF) was obtained: Calcd for C 28 H 36 NaO3Si + [M+Na] + :471.2326, found 471.2338.

[0173] Example 17 Synthesis of Compound Ic

[0174]

[0175] The substrate in Example 15 was replaced by compound 3-c from compound 1-a to obtain compound Ic with a yield of 94.41%. High-resolution mass spectrometry test of compound Ic was performed, and HRMS (ESI-TOF) was obtained: Calcd for C 29 H 38 NaO3Si + [M+Na] + :485.2482,found485.2493.

[0176] Example 18 Synthesis of Compound Id

[0177]

[0178] The substrate in Example 15 was replaced by compound 4-d from compound 1-a to obtain compound Id with a yield of 92.21%. High-resolution mass spectrometry was performed on compound Id to obtain HRMS (ESI-TOF): Calcd for C 30 H 40 NaO3Si + [M+Na] + :499.2639,found 499.2658.

[0179] Example 19 Synthesis of Compound Ie

[0180]

[0181] The substrate in Example 15 was replaced by compound 5-e from compound 1-a to obtain compound 1e with a yield of 94.39%. Compound 1e was subjected to high-resolution mass spectrometry test and HRMS (ESI-TOF) was obtained: Calcd for C 29 H 38 NaO3Si + [M+Na] + :485.2482, found 485.2499.

[0182] Example 20 Synthesis of Compound Ie

[0183]

[0184] The substrate in Example 15 was replaced by compound 6-f from compound 1-a to obtain compound If with a yield of 92.51%. High-resolution mass spectrometry test was performed on compound If, and HRMS (ESI-TOF) was obtained: Calcd for C 29 H 36NaO3Si + [M+Na] + :483.2326,found483.241.

[0185] Example 21 Synthesis of Compound IIa

[0186]

[0187] Preparation of Rh[(COD)(Sc,Rp)-Duanphos)]SbF6 catalyst:

[0188] In a glove box filled with argon, [Rh(COD)Cl]2 (0.2 mmol, 1.0 equiv.) and AgSbF6 (0.4 mmol, 2.0 equiv.) and acetone (10 mL) were added to a dry round-bottom flask in sequence, and the reaction was stirred at room temperature for 20 minutes to obtain a yellow suspension. Under argon protection, (Sc, Rp)-Duanphos (0.4 mmol) was added to the yellow suspension, stirred for 20 minutes, and then distilled under reduced pressure to obtain 0.4 mmol of rhodium catalyst [Rh((COD)(Sc, Rp)-Duanphos)]SbF6.

[0189] Catalytic synthesis of compound IIa:

[0190] In an argon-filled glove box, substrate compound Ia (4.0 mmol, 1.0 equiv) was dissolved in degassed 1,2-dichloroethane (DCE, 18 mL), and the above-prepared [Rh((COD)(Sc,Rp)-Duanphos)]SbF6 (0.2 mmol, 0.05 equiv) dissolved in 2.0 mL of DCE was added at room temperature, and the mixture was stirred at 50 °C for 8 h.

[0191] After the reaction was completed, the resulting mixture was concentrated under vacuum and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 100 / 1 to 80 / 1) to give compound IIa (yield 85%, >20:1 enantiomeric selectivity) as a yellow oil.

[0192] 1H NMR (600MHz, CDCl3) δ7.85-7.82(m,1H),7.51-7.44(m,2H),7.39(t,J=7.5Hz,2H),7.36- 7.30(m,2H),7.28-7.25(m,1H),7.02-6.97(m,1H),6.53(d,J=2.6Hz,1H),5.79-5.70(m,1 H),5.40-5.24(m,2H),5.12(s,2H),4.13(dt,J=7.9,6.8Hz,1H),3.56-3.35(m,1H),2.75( dd,J=17.6,6.7Hz,1H),2.46(dd,J=17.6,7.9Hz,1H),0.90(s,9H),0.08(d,J=3.6Hz,6H);

[0193] 13 C NMR (150MHz, CDCl3) δ202.1,158.6,139.0,137.7,137.5,137.2,135.9,129.1,128.7,12 8.1,127.8,124.1,119.5,117.4,115.9,72.4,70.2,59.4,49.0,25.9,18.2,-4.4,-4.5;

[0194] HRMS(ESI-TOF):Calcd for C 27 H 35 O3Si + [M+H] + :435.2350, found 435.2346; [α] 25 D = -63.5 (c 0.84, CH2Cl2).

[0196] Example 22 Synthesis of Compound IIb

[0197]

[0198] The substrate compound Ia in Example 21 was replaced by compound Ib to obtain compound IIb with a yield of 81.11%. Compound IIb was subjected to high-resolution mass spectrometry test and HRMS (ESI-TOF) was obtained: Calcd for C 28 H 37 O3Si + [M+H] + :449.2503, found 449.2521;.

[0199] Example 23 Synthesis of Compound IIc

[0200]

[0201] The substrate compound Ia in Example 21 was replaced by compound Ic to obtain compound IIc with a yield of 77.91%. Compound IIc was subjected to high-resolution mass spectrometry test and HRMS (ESI-TOF) was obtained: 29 H 39 O3Si + [M+H] + :463.2590,found463.2672;.

[0202] Example 24 Synthesis of Compound IId

[0203]

[0204] The substrate compound Ia in Example 21 was replaced by compound Id to obtain compound IId with a yield of 84.82%. Compound IId was subjected to high-resolution mass spectrometry test and HRMS (ESI-TOF) was obtained: Calcd for C 30 H 41 O3Si + [M+H] + :477.2816, found 477.2832;.

[0205] Example 25 Synthesis of Compound IId

[0206]

[0207] The substrate compound Ia in Example 21 was replaced by compound Ie to obtain compound IIe with a yield of 80.58%. Compound IIe was subjected to high-resolution mass spectrometry test and HRMS (ESI-TOF) was obtained: Calcd for C 29 H 39 O3Si + [M+H] + :463.2659, found 463.2671;.

[0208] Example 26 Synthesis of Compound IIf

[0209]

[0210] The substrate compound Ia in Example 21 was replaced by compound If to obtain compound IIf with a yield of 84.09%. Compound IIf was subjected to high-resolution mass spectrometry test and HRMS (ESI-TOF) was obtained: Calcd for C 29 H 37 O3Si + [M+H] + :461.2503,found461.2515;.

[0211] Example 27 Synthesis of Compound IIIa

[0212]

[0213] CuI (3.0 mmol, 2.0 equivalents) was suspended in a THF-HMPA mixed solvent (4:1, 7.5 mL), and DIBAL-H (3.0 mL, 1.0 M in hexane, 2.0 equivalents) was added at -78 ° C. After the resulting suspension was stirred for 10 minutes, a solution of substrate compound IIa (1.5 mmol) dissolved in THF (4.0 mL) was added through a cannula at -78 ° C.

[0214] After the mixture was stirred at -50°C for 1 hour, 2M aqueous hydrochloric acid solution (0.8 mL) was added. After 30 minutes, the reaction mixture was diluted with ether (Et2O) and filtered through Celite, the aqueous phase was separated and extracted with ether. The combined organic layer was washed with water and saturated brine in turn, and then dried over anhydrous magnesium sulfate (MgSO4).

[0215] After concentration under reduced pressure, the crude product was purified by column chromatography (petroleum ether / ethyl acetate = 80 / 1 to 30 / 1) to give IIIa (yield 78%) as a colorless oil.

[0216] 1H NMR (400MHz, CDCl3) δ7.45-7.42(m,2H),7.39(t,J=7.6Hz,2H),7.35-7.30(m,1H),7.17(t,J=7.9Hz,1H),6.86-6.79(m,1H) ,6.78(t,J=2.0Hz,1H),6.75(dt,J=7.6,1.2Hz,1H),5.68-5.60(m,1H),5.13(dd,J=10.3,1.6Hz,1H),5.09(dt,J=17.1,1.2H z,1H),5.04(s,2H),4.03(td,J=8.3,7.0Hz,1H),3.02(dd,J=14.0,5.4Hz,1H),2.86(dd,J=14.0,5.6Hz,1H),2.61(ddd,J=18 .2,7.0,1.3Hz,1H),2.45-2.38(m,1H),2.35-2.27(m,1H),2.07(dd,J=18.3,8.5Hz,1H),0.87(s,9H),0.04(d,J=5.2Hz,6H);

[0217] 13 C NMR (150MHz, CDCl3) δ215.0,158.9,140.6,138.0,137.2,129.4,128.7,128.0,127.6,1 22.5,117.8,116.2,113.1,73.0,69.9,55.2,53.8,47.6,33.3,25.9,18.2,-4.5,-4.6;

[0218] HRMS(ESI-TOF):Calcd for C 27 H 36 NaO3Si + [M+Na] + :459.2326, found 459.2321;

[0219] [α] 23 D = -53.1 (c 1.60, CH2Cl2).

[0220] Example 28 Synthesis of Compound IIIb

[0221]

[0222] The substrate compound IIa used in Example 27 was replaced by compound IIb to obtain compound IIIb with a yield of 72.45%. Compound IIIb was subjected to high-resolution mass spectrometry test and HRMS (ESI-TOF) was obtained: Calcd for C 28 H 38 NaO3Si + [M+Na] + :473.2482, found 473.2497.

[0223] Example 29 Synthesis of Compound IIIc

[0224]

[0225] The substrate compound IIa used in Example 27 was replaced by compound IIc to obtain compound IIIc with a yield of 76.51%. Compound IIIc was subjected to high-resolution mass spectrometry test and HRMS (ESI-TOF) was obtained: Calcd for C 29 H 40 NaO3Si + [M+Na] + :487.2639, found 487.2649.

[0226] Example 30 Synthesis of Compound IIId

[0227]

[0228] The substrate compound IIa used in Example 27 was replaced by compound IId to obtain compound IIId with a yield of 70.22%. Compound IIId was subjected to high-resolution mass spectrometry test and HRMS (ESI-TOF) was obtained: Calcd for C 30 H 42 NaO3Si + [M+Na] + :501.2795, found 501.2811.

[0229] Example 31 Synthesis of Compound IIIe

[0230]

[0231] The substrate compound IIa used in Example 27 was replaced by compound IIe to obtain compound IIIe with a yield of 75.92%. Compound IIIe was subjected to high-resolution mass spectrometry test and HRMS (ESI-TOF) was obtained: Calcd for C 29 H 40 NaO3Si+ [M+Na] + :487.2639,found 487.2658.

[0232] Example 32 Synthesis of Compound IIIf

[0233]

[0234] The substrate compound IIa used in Example 27 was replaced by compound IIf to obtain compound IIIf with a yield of 76.92%. Compound IIIf was subjected to high-resolution mass spectrometry test and HRMS (ESI-TOF) was obtained: Calcd for C 30 H 40 NaO3Si + [M+Na] + :499.2639,found 499.2662.

[0235] Example 33 Synthesis of Compound IIIg

[0236]

[0237] The substrate compound IIa used in Example 27 was replaced by compound IIg to obtain compound IIIg with a yield of 72.01%. Compound IIIg was subjected to high-resolution mass spectrometry test and HRMS (ESI-TOF) was obtained: Calcd for C 31 H 44 NaO3Si + [M+Na] + :515.2952,found 515.2972.

[0238] Example 34 Synthesis of Compound IVa

[0239]

[0240] Compound IIIa (0.3mmol, 1.0 equivalent) was dissolved in DCE (0.6mL), followed by the addition of Hoveyda-Grubbs catalyst (0.03mmol, 0.1 equivalent, dissolved in DCE, 0.6mL) and compound C (3.0mmol, 10.0 equivalent, dissolved in anhydrous DCE, 3.0mL). The reaction mixture was stirred overnight under reflux conditions. After cooling to room temperature, the reaction mixture was concentrated in vacuo and separated by silica gel column chromatography (petroleum ether / ethyl acetate=80 / 1 to 40 / 1). IVa (42% yield) was finally obtained as a colorless oil.

[0241] 1H NMR(600MHz,CDCl3)δ7.42(d,J=7.3Hz,2H),7.37(t,J=7.5Hz,2H),7.31(t,J=7.3Hz,1H),7.15(t,J=7.9Hz,1H),6.80(dd,J=8.2,1.9Hz,1H),6.77(s,1H),6.73(d,J=7.5Hz,1H),5.54(dd,J=15.5,5.1Hz,1H),5.47(dd,J=15.6,7.6Hz,1H),5.02(s,2H),4.11-4.00(m,2H),3.04(dd,J=14.0,5.3Hz,1H),2.79(dd,J=14.0,5.8Hz,1H),2.59(dd,J=18.0,6.6Hz,1H),2.42(dt,J=10.3,7.5Hz,1H),2.27(dt,J=10.7,5.4Hz,1H),2.04(dd,J=18.2,8.0Hz,1H),1.49-1.26(m,8H),0.91-0.84(m,21H),0.10-0.02(m,12H).

[0242] 13 C NMR(150MHz,CDCl3)δ215.38,158.78,140.52,137.08,136.61,129.27,128.52,128.43,127.85,127.44,122.31,115.98,112.85,73.34,72.69,69.79,55.14,51.65,47.68,38.49,33.29,31.85,25.89,25.09,22.62,18.22,18.04,14.05,-4.24,-4.66,-4.70.

[0243] HRMS(ESI-TOF):Calcd for C 39 H 62 NaO4Si2 + [M+Na] + :673.4079,found 673.4077;

[0244] [α] 23 D =-22.3(c 0.96,CH2Cl2).

[0245] The above description is only a preferred embodiment of the present application and is not intended to limit the protection scope of the present application. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present application are included in the protection scope of the present application.

Claims

1. A treprostinil intermediate derivative, such as formula I: The carbon atom marked with * is an R configuration, an S configuration, or an achiral carbon atom; The R 1 Selected from H, a hydroxyl protecting group; The R 2 is selected from substituted or unsubstituted alkyl; The R 3 and R 4 are each independently selected from hydrogen, substituted or unsubstituted alkyl, or, The R 3 and R 4 Together with the atoms to which they are attached, they form the ring Ar, The ring Ar is selected from substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl.

2. A treprostinil intermediate derivative, such as formula: It is stated represents a single bond or a double bond; The carbon atom marked with * is an R configuration, an S configuration, or an achiral carbon atom; The R 1 Selected from H, a hydroxyl protecting group; The R 2 is selected from substituted or unsubstituted alkyl; The R 3 and R 4 are each independently selected from hydrogen, substituted or unsubstituted alkyl, or, The R 3 and R 4 Together with the atoms to which they are attached, they form the ring Ar, The ring Ar is selected from substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl.

3. A treprostinil intermediate derivative, specifically as follows:

4. A method for synthesizing the intermediate of formula I, comprising: Under an inert atmosphere, compound B is dissolved in an organic solvent, a lithium reagent is added to obtain a reaction mixture, and a substrate of formula V is added to the reaction mixture to react to obtain a compound of formula I, such as: The lithium reagent is selected from one or a combination of n-butyl lithium, isobutyl lithium, tert-butyl lithium, methyl lithium, phenyl lithium, diisopropyl lithium amide, and 2,2,6,6-tetramethylpiperidinium lithium; The carbon atom marked with * is an R configuration, an S configuration, or an achiral carbon atom; The R 1 Selected from H, a hydroxyl protecting group; The R 2 is selected from substituted or unsubstituted alkyl; The R 3 and R 4 are each independently selected from hydrogen, substituted or unsubstituted alkyl, or, The R 3 and R 4 Together with the atoms to which they are attached, they form the ring Ar, The ring Ar is selected from substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl.

5. A method for synthesizing an intermediate of formula II, comprising: In an inert atmosphere, the compound of formula I is dissolved in an organic solvent, a catalyst is added, and the reaction is performed to obtain a product of formula II, such as: The carbon atom marked with * is an R configuration, an S configuration, or an achiral carbon atom; The R 1 Selected from H, a hydroxyl protecting group; The R 2 is selected from substituted or unsubstituted alkyl; The R 3 and R 4 are each independently selected from hydrogen, substituted or unsubstituted alkyl, or, The R 3 and R 4 Together with the atoms to which they are attached, they form ring Ar; The ring Ar is selected from substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl; The catalyst is obtained by adding a ligand, an additive and a metal precursor into an organic solvent. The ligand structure of the catalyst is as follows: The metal precursor is selected from one of [Rh(COD)Cl]2, [Rh(ethylene)Cl]2, and [Rh(NBD)Cl]2; The additive is selected from AgSbF6, AgOTf or AgBF4.

6. The method for synthesizing the intermediate of formula II according to claim 5, characterized in that: The inert atmosphere is selected from nitrogen or argon or a mixture thereof, and / or, 0.20-0.25 mol of the compound of formula I is added to every 1 L of organic solvent, and / or, 0.008-0.012 mol of the catalyst is added to every 1 L of organic solvent, and / or, the reaction temperature is 45-55°C.

7. A method for synthesizing an intermediate of formula III, comprising: The compound of formula II is added into a reaction system consisting of a catalyst, a reducing agent and an organic solvent to obtain a compound of formula III; The R 1 Selected from H, a hydroxyl protecting group; The R 2 is selected from substituted or unsubstituted alkyl; The R 3 and R 4 are each independently selected from hydrogen, substituted or unsubstituted alkyl, or, The R 3 and R 4 Together with the atoms to which they are attached, they form the ring Ar, The ring Ar is selected from substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl; The carbon atom marked with * is an R configuration, an S configuration, or an achiral carbon atom.

8. The method for synthesizing the intermediate of formula III according to claim 7, characterized in that: The catalyst is selected from one or a combination of cuprous chloride, cuprous bromide or cuprous iodide, and / or the organic solvent is selected from one or a combination of toluene, chlorobenzene, tetrahydrofuran, and hexamethylphosphamide, and / or the reducing agent is selected from one or a combination of diisobutylaluminum hydride, red aluminum, trimethylsilane or triphenylsilane, and / or the organic solvent includes THF and HMPA, and the volume ratio of THF and HMPA is (2-3):1, and / or the feed ratio of the reducing agent to the catalyst is (1.5-2.5):2, and / or the feed ratio of the compound II to the catalyst is 1:(1.8-2.3).

9. A method for synthesizing an intermediate represented by formula IV, characterized in that: include: The compound of formula III is dissolved in an organic solvent, and then a Hoveyda-Grubbs catalyst and compound C are added to react to obtain a compound of formula IV; The carbon atom marked with * is an R configuration, an S configuration, or an achiral carbon atom; The R 1 Selected from H, a hydroxyl protecting group; The R 2 is selected from substituted or unsubstituted alkyl groups.

10. A method for synthesizing an intermediate derivative represented by formula V, characterized in that: include: Compound S1 is put into an organic solvent, a catalyst and KOMe are added, and the reaction is carried out under a hydrogen atmosphere to obtain a compound of formula 1; The R 1 Selected from H or a hydroxyl protecting group; The R 2 is selected from substituted or unsubstituted alkyl; The R 3 and R 4 are each independently selected from hydrogen, substituted or unsubstituted alkyl, or, The R 3 and R 4 Together with the atoms to which they are attached, they form the ring Ar, The ring Ar is selected from substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl; The carbon atom marked with * is an R configuration, an S configuration, or an achiral carbon atom; The catalyst is obtained by complexing a ligand with a metal precursor in an organic solvent. The ligand structure of the catalyst is as follows: The metal precursor is [Ir(COD)Cl]2.

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