TW201425323A - Intermediates for synthesizing treprostinil and preparation method thereof as well as the preparation method of treprostinil thereby - Google Patents

Abstract

The present invention relates to intermediates for synthesizing treprostinil (formula I) and preparation method thereof as well as the preparation method of treprostinil thereby. Specifically, the invention relates to intermediate of formula (VI), its preparation and its application for the synthesis of treprostinil. The preparation method of treprostinil includes the reduction of intermediate of formula (VI) followed by removal of hydroxyl protecting group to give intermediate of formula (III) and reaction of the intermediate of formula (III) with chloroacetonitrile followed by hydrolysis to afford treprostinil of formula(I). The present method is practical, highly efficient, and suitable for industrial production.

Description

Intermediate for preparing trepronil, preparation method thereof and method for preparing trepronil by using same

The present invention relates to an intermediate for the preparation of Treprostinil, a process for the preparation thereof, and a process for the preparation of Treprostinil by means of the same.

Pulmonary hypertension is a group of clinical pathophysiological syndromes in which the mean pulmonary artery pressure measured by the right heart catheter is greater than or equal to 25 mmHg at rest in various conditions. As a common clinical cardiovascular disease, pulmonary hypertension is caused by vasospasm of the pulmonary arterioles, intimal hyperplasia and remodeling leading to increased pulmonary vascular resistance, which can eventually lead to right heart failure and even death.

As a target drug for the treatment of pulmonary hypertension, prostacyclin (PGI2) can promote pulmonary vasodilation, inhibit platelet aggregation and thrombosis, stimulate thrombolysis, inhibit pulmonary vascular remodeling, thereby reducing pulmonary artery pressure and pulmonary vascular resistance, and pulmonary hypertension Has a significant effect. In 2003, Flolan, which is based on the sodium salt of PGI2, was the first prostacyclin approved by the US Food and Drug Administration (FDA) for the treatment of pulmonary hypertension. However, since PGI2 has a half-life of about 10 minutes in an environment of 25 degrees Celsius and pH 7.6, epoprostenol has a circulation in the human body. The duration of action is 3-5 minutes, so this treatment requires continuous intravenous administration and is stored at low temperature and protected from light before infusion. This limits the widespread use of epoprostenol to a certain extent and also facilitates the exploration of PGI2 derivatives with better stability and biological activity. Considering that the hydrolysis of alkenyl ethers in the PGI2 structure in a weak acid environment may be the main cause of PGI2 instability, scientific researchers have sought to find chemically stable alternative derivatives by modifying or altering the alkenyl ether. By replacing the alkenyl ether with a functional group of a phenol ether, it has been found that Treprostinil (chemical structure as shown in formula (I)) is a suitable substitute for the treatment of pulmonary hypertension. Precursor has excellent stability, with a half-life of 4 hours in the circulation, no decomposition at 25 degrees C for five years, and no decomposition of the drug through the lungs. At the same time, treprostinil has good biological activity and has good curative effect in the treatment of pulmonary hypertension, peripheral vascular disease, ischemic disease, treatment of improving renal function, neuropathic foot ulcer, asthma and even treatment of cancer. In particular, in the treatment of pulmonary hypertension, Remodulin, a new drug containing the sodium salt of trepronil, was approved by the US Food and Drug Administration (FDA) in 2004.

Since the Treprostinil has a fused ring structure and has multiple chiral centers, the synthesis process is complicated. Aristoff et al. first reported the synthesis of Treprostinil ( Tetrahedron Lett. 1982, 23 , 2067-2070), whose synthesis strategy was to first synthesize the C ring (five-membered ring) and then pass the 1,4-addition reaction. A ring (aromatic ring) is introduced, and finally the Friedel-Crafts reaction is closed to form a B ring (six-membered ring) (as shown in Scheme 1). Multistage synthesis gives compound 1, olefination reaction converts ketone in compound 1 to olefin 2; hydroboration reaction yields compound 3 from a small frontal attack with less steric hindrance, while constructing a chiral center on the C ring; Friedel-Crafts The reaction loop was constructed to form a B-ring, which ultimately succeeded in synthesizing the main skeleton of Treprostinil. This chiral synthesis route requires a total of 36 steps of reaction, which is too long and is not conducive to large-scale synthesis.

Subsequently, Aristoff et al. developed another synthetic method ( J. Am. Chem. Soc. 1985, 107 , 7967-7974) by introducing the A ring and the B ring by the commercially available starting material 5, and then using Wadsworth-Emmons. -Wittig reaction to synthesize the C ring (as shown in Scheme 2). The compound 6 is obtained by the carbonylation of the compound 5; the allylation of the carbonyl group, followed by the decarbonylation of the carbonyl group to give the racemic compound 7; the olefin is oxidized to give the lactone 8; the Wadsworth-Emmons-Wittig reaction is finally formed. The C ring (no chirality), the hydrogenation reaction and the reduction of sodium borohydride under basic conditions determine the other two chiral centers on the C ring, thereby constructing the main skeleton of the trepronil. This synthetic route has a total of fourteen steps of reaction, and the synthesis is relatively simple, but the obtained racemic tromethamine is obtained. Since no suitable chiral resolving agent is found, optically pure treprostinil cannot be synthesized in a large amount.

Based on the Aristoff synthesis method, Fuchs et al. reported a method for the synthesis of Treprostinil ( Bioorg. Med. Chem. Lett. 1991, 1 , 79-82), which was synthesized by first synthesizing the C ring and then The 1,4-addition reaction introduces the A ring, which is again closed by a 1,4-addition reaction to form a B ring (as shown in Scheme 3). Multi-step synthesis of chiral compound 13, a 1,4-addition reaction with copper reagent 12 introduced into the A ring; deprotection to form mercapto chloride 15; a further 1,4-addition reaction ring closure to form a B ring to obtain compound 16; Finally, the dephenylsulfonyl group can successfully construct the main skeleton of Treprostinil (2:1 cis-trans isomer ratio). This chiral synthesis route is relatively short, but during the reaction of the dephenylsulfonyl group, the chiral center on the C ring is eliminated, and only a 2:1 cis-trans isomer ratio is obtained, since no cost-effective separation means is found. It is also impossible to synthesize optically pure Pre-Lenin.

Moriarty et al. reported a method for synthesizing Treprostinil using the Pauson-Khand cyclization reaction ( J. Org. Chem. 2004, 69 , 1890-1902). The synthesis strategy is: introducing the A ring by using commercially available raw materials, and then The B-ring and C-ring were simultaneously constructed using the Pauson-Khand cyclization reaction (as shown in Scheme 4). A chiral center was constructed by asymmetric reduction of CBS of compound 18 obtained by multi-step synthesis to obtain cyclization reaction precursor compound 19; Pauson-Khand cyclization reaction gave B ring and C ring, and at the existing chiral center Another chiral center on the C ring was constructed by hydrogenation reduction; the chiral control group of the oxime was removed by hydrogenation reduction, and the unsaturated ketene was reduced to obtain the cis compound 21 (the positive and negative of the ortho position of the carbonyl group of 4:1) Isomerization); the reduction of sodium borohydride under alkaline conditions reduces both the carbonyl group and the chiral center of its ortho position, thereby obtaining the main skeleton of Treprostinil. This chiral synthesis route has good chiral control, but requires an excessive amount of expensive chiral CBS reagent and octacarbonyl bis-cobalt, which is relatively expensive to synthesize.

Due to the medical significance of Quran Lenier and the synthetic complexity of the Pre-Lenin molecule, there is an urgent need to develop more effective methods for large-scale production.

The present invention provides a compound represented by the formula (VI) which can be used for the preparation of kojiprene,

Wherein P ¹ , P ² and P ³ are each independently hydrogen or a hydroxy protecting group; preferably P ¹ is hydrogen, substituted or unsubstituted C _1-10 alkyl, P ² is hydrogen, substituted or unsubstituted C _1-10 alkyl, P ³ is hydrogen or -SiR ¹ R ² R ³ , wherein R ¹ , R ² and R ³ are each a C _1-10 straight or branched alkyl group, C _3-10 A cycloalkyl group, or a substituted or unsubstituted C _6-10 aryl group.

Another aspect of the present invention provides a process for the preparation of the compound (VI) which can employ the following synthetic route.

Wherein P ¹ , P ² and P ³ are each independently hydrogen or a hydroxy protecting group; preferably P ¹ is hydrogen, substituted or unsubstituted C _1-10 alkyl, P ² is hydrogen, substituted or unsubstituted C _1-10 alkyl, P ³ is hydrogen or -SiR ¹ R ² R ³ , wherein R ¹ , R ² and R ³ are each a C _1-10 straight or branched alkyl group, C _3-10 A cycloalkyl group, or a substituted or unsubstituted C _6-10 aryl group.

Compound (VI) can be obtained by reacting compound (VII) with dicobalt octacarbonyl (Co ₂ (CO) ₈ ) (Pauson-Khand reaction, reference: J. Org. Chem. 2004, 69 , 1890); By reacting compound (VII) with carbon monoxide under the catalysis of palladium chloride (palladium-catalyzed Pauson-Khand reaction, reference: J. Org. Chem. 2009, 74 , 1657), palladium-catalyzed Pauson-Khand reaction can be avoided The expensive hazardous reagent octacarbonylcobalt is used to make the synthesis process safer and reduce the cost of synthesis.

In a preferred embodiment of the invention, in formulae (VI) and (VII), P ^{1 is} preferably THP, P ^{2 is} preferably benzyl, and P ³ is TBS.

The invention also provides a novel method for synthesizing treprostinil starting from compound (VI), that is, compound (VI) is subjected to palladium carbon catalytic hydrogenation reduction to obtain compound (V), and compound (V) is hydroborated. After sodium reduction and removal of the protecting group, the compound (III) is obtained, and the compound (III) is reacted with chloroacetonitrile and then hydrolyzed to prepare the trepronil.

Wherein P ¹ , P ² and P ³ are each independently hydrogen or a hydroxy protecting group; preferably P ¹ is hydrogen, substituted or unsubstituted C _1-10 alkyl, P ² is hydrogen, substituted or unsubstituted C _1-10 alkyl, P ³ is hydrogen or -SiR ¹ R ² R ³ , wherein R ¹ , R ² and R ³ are each a C _1-10 straight or branched alkyl group, C _3-10 A cycloalkyl group, or a substituted or unsubstituted C _6-10 aryl group.

Compound (VII) is obtained by protecting the hydroxy group of compound (VIII),

Wherein P ¹ and P ² are each independently hydrogen or a hydroxy protecting group; preferably P ¹ is hydrogen, substituted or unsubstituted C _1-10 alkyl, P ² is hydrogen, substituted or unsubstituted C _{1- 10} alkyl.

According to still another aspect of the present invention, there is provided a compound of the formula (VIII) and a process for the preparation thereof, wherein the compound of the formula (VIII) can be used for the preparation of treprostinil.

Wherein P ¹ and P ² are each independently hydrogen or a hydroxy protecting group; preferably P ¹ is hydrogen, substituted or unsubstituted C _1-10 alkyl, P ² is hydrogen, substituted or unsubstituted C _{1- 10} alkyl.

In the method for producing the compound (VIII) provided by the present invention, the compound (VIII) can be obtained by reacting the compound (X) with the compound (X) by the compound (IX) under the action of a chiral compound and an organozinc compound,

Wherein P ¹ and P ² are each independently hydrogen or a hydroxy protecting group; preferably P ¹ is hydrogen, substituted or unsubstituted C _1-10 alkyl, P ² is hydrogen, substituted or unsubstituted C _{1- 10} alkyl.

The organozinc compound is ZnR' ₂ , wherein R' is a substituted or unsubstituted C _1-6 alkyl group, preferably a methyl group.

The chiral compound is a compound as shown in formula XIII.

Wherein Ar ¹ and Ar ² are a substituted or unsubstituted aryl group selected from a phenyl group or a naphthyl group, which is optionally 1 to 5 selected from the group consisting of halogen, trifluoromethyl, methoxy, and amine groups. Substituted with a substituent of a cyano group, a nitro group, a phenyl group or a C _1-6 alkyl group; R is a substituted or unsubstituted C _1-6 alkyl group, preferably R is a methyl group.

In a preferred embodiment of the present invention, in the formulae (X) and (VIII), P ¹ is THP; in the formulae (X) and (VIII), P ² is a benzyl group; in the formula XIII, Ar ¹ and Ar ² is a phenyl group, R is a methyl group, and the organozinc reagent used is dimethyl zinc.

Compound (IX) can be synthesized by reference to the literature: J. Am. Chem. Soc. 1985, 107 , 1421.

Compound XIII can be synthesized by reference to the literature: Tetrahedron: Asymmetry 2005, 16 , 1953.

By this method, the chiral intermediate (VIII) can be synthesized in one step from the compounds (IX) and (X), thereby avoiding the multi-step reaction in the Moritary synthesis method (ie, first addition, reoxidation, and then CBS). Asymmetric reduction) avoid the use of expensive CBS reagents. Therefore, the method improves the synthesis efficiency and reduces the synthesis cost.

Compound (VIII) can also be synthesized by the following synthesis methods.

The method comprises the steps of: 1) reacting a compound (X) with a compound (IX) under a base to obtain a compound (XIV), 2) oxidizing the compound (XIV) to obtain a compound (XV), and 3) a compound (XV). Asymmetric reduction under the action of a chiral reagent gives compound (VIII).

The base in step 1) is an organolithium compound, preferably n-butyllithium; in step 2) the oxidation reaction can be Swern oxidation or oxidation by pyridinium chlorochromate; the chiral reagent in step 3) is ( R )-CBS reagent.

The use of CBS reagents to control asymmetric reduction is a common method for the reduction of ketones to chiral alcohols, see the literature: J. Am. Chem. Soc. 1987, 109 , 5551.

The present invention also provides a compound represented by formula (X) and a process for the preparation thereof, wherein a compound represented by formula (X) can be used for the preparation of treprostinil.

Wherein P ¹ is hydrogen or a hydroxy protecting group, preferably P ¹ is hydrogen, substituted or unsubstituted C _1-10 alkyl.

The preparation method of the compound (X) can be carried out by the following synthesis method.

Wherein P ¹ is hydrogen or a hydroxy protecting group, preferably P ¹ is hydrogen, substituted or unsubstituted C _1-10 alkyl; R ⁴ is -SiR ¹ R ² R ³ wherein R ¹ , R ² and R ³ Each is a C _1-10 linear or branched alkyl group, a C _3-10 cycloalkyl group, a substituted or unsubstituted C _6-10 aryl group.

The method comprises the steps of: 1) reacting compound (XVI) with compound (XII) under the action of a base to obtain compound (XI), and 2) compound (XI) obtaining compound (X) under the action of a base.

The base in the step 1) is an organolithium compound, preferably n-butyllithium; the base in the step 2) is an inorganic base, preferably sodium hydroxide.

Compound (XII) can be synthesized by reference to the literature: Tetrahedron , 2010, 66 , 2351.

The present invention also provides a compound represented by the formula (XI),

Wherein P ¹ and R ^{4 are} as defined in the compound (X).

The preparation method of the trepronil of the invention has the characteristics of safe operation, high synthesis efficiency, low synthesis cost, and is suitable for industrial production, and has significant social and economic benefits.

The terminology used in the present invention has the following meanings, unless stated to the contrary:

"Alkyl" means a saturated aliphatic hydrocarbon group comprising straight and branched chain groups of 1 to 10 carbon atoms, preferably 1 to 6 carbon atoms. Non-limiting examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, t-butyl, n-pentyl, 1, 1-di Methylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1 -ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethyl Butyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl Wait. The alkyl group may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment, preferably one or more of the following groups, independently selected from alkyl, alkenyl. , alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy a heterocycloalkoxy group, a cycloalkylthio group, a heterocycloalkylthio group, a pendant oxy group.

"Cycloalkyl" means a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent comprising from 3 to 10 carbon atoms, preferably C _3-8 cycloalkyl, more preferably C _3-6 ring The alkyl group is preferably a 5- or 6-membered cycloalkyl group. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptene Alkenyl, cyclooctyl and the like. Polycyclic cycloalkyl groups include spiro, fused, and bridged cycloalkyl groups. The cycloalkyl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkoxy, halogen, hydroxy, nitro, cyano. , cycloalkyl, heterocycloalkyl, aryl, heteroaryl.

"Aryl" means a 6 to 14 membered all-carbon monocyclic or fused polycyclic ring (i.e., a ring that shares a pair of adjacent carbon atoms) having a conjugated π-electron system, preferably 6 to 10 members, more preferably Good phenyl and naphthyl. The aryl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, Alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, Heterocycloalkylthio.

"Hydroxy protecting group" is a suitable group for hydroxyl protection known in the art, see the hydroxy protecting group in the literature ("Protective Groups in Organic Synthesis", 5 ^Th Ed. TW Greene & PGM Wuts). By way of example, preferably, the hydroxy protecting group may be (C _1-10 alkyl or aryl) ₃ fluorenyl, for example: triethyl decyl, triisopropyl decyl, tert-butyl dimethyl Anthracenyl, tert-butyldiphenylfluorenyl, etc.; may be a C _1-10 alkyl or substituted alkyl group, for example: methyl, tert-butyl, allyl, benzyl, methoxymethyl, Ethoxyethyl, 2-tetrahydropyranyl (THP), etc.; may be (C _1-10 alkyl or aryl) fluorenyl, for example: formazan, ethyl benzyl, benzhydryl, etc.; It may be (C _1-6 alkyl or C _6-10 aryl)sulfonyl; it may also be (C _1-6 alkoxy or C _6-10 aryloxy)carbonyl.

The present invention will be described in detail below with reference to the specific embodiments thereof.

The following table shows the structural formula of the compounds involved in the examples.

Example 1: Preparation of Compound Xa

To a solution of 1-(trimethyldecyl)propyne (XVIa, purchased from Shanghai Ruiyi Pharmaceutical Technology Co., Ltd.) (74 g) in anhydrous tetrahydrofuran (200 ml) at 0 ° C under n. Lithium (250 ml, 2.5 M hexane solution). After stirring at 0 ° C for 3 hours, a solution of compound XIIa (65.8 g, Ref.: Tetrahedron 2010, 66, 2351) in anhydrous tetrahydrofuran (100 ml) was added dropwise, and the reaction mixture was slowly warmed to 20 ° C and stirred at 20 ° C. 12 hours. The reaction was quenched with aq. aq. The organic phase was concentrated to give the crude product XIa as a yellow oil.

Under a nitrogen atmosphere, sodium hydroxide (39.2 g) was slowly added to a solution of the crude product XIa in ethanol at 20 °C. After stirring at 20 ° C for 12 hours, the reaction mixture was concentrated. Compound Xa (59 g, a two-step yield of 88%) was obtained by column chromatography.

^{Xa: 1 H NMR (400MHz,} CDCl 3) δ 5.80 (ddd, J = 17.1,10.1,6.9Hz, 1H), 4.98 (dd, J = 22.2,13.1Hz, 2H), 4.65 (dd, J = 6.9, 4.0 Hz, 1H), 3.90 (dd, J = 10.7, 6.2 Hz, 1H), 3.73 (dd, J = 10.3, 4.3 Hz, 1H), 3.50 (dd, J = 11.0, 5.6 Hz, 1H), 2.33 ( Dt, J = 7.5, 4.0 Hz, 1H), 2.24 (td, J = 7.3, 2.5 Hz, 1H), 2.05 (dd, J = 13.5, 6.8 Hz, 2H), 1.93 (dt, J = 5.3, 2.6 Hz) , 1H), 1.82-1.30 (m, 12H).

Example 2: Preparation of Compound VIIIa

To a solution of compound Xa (47.3 g) in toluene (200 ml) was added to a toluene solution of hexane (200 ml, 1.0 M) at 20 ° C under nitrogen, and then compound XIIIa (3.80 g, Tetrahedron: Asymmetry 2005, 16, 1953) in toluene solution. The mixture was cooled to -10 ° C, and a toluene solution of Compound IXa (12.6 g, J. Am. Chem. Soc. 1985, 107, 1421) was added dropwise. After stirring at -10 ° C for 6 hours, the reaction was quenched with saturated aqueous ammonium chloride. The organic phase was concentrated and purified by column chromatography to afford Compound VIIIa (23.2 g, yield 95%).

VIIIa: ¹ H NMR (400MHz, CDCl ₃ ) δ 7.46-7.16 (m, 7H), 6.91 (d, J = 8.2 Hz, 1H), 6.05-5.95 (m, 1H), 5.87-5.71 (m, 1H) , 5.64 (s, 1H), 5.08 (s, 2H), 5.05-4.89 (m, 4H), 4.70-4.60 (m, 1H), 3.90-3.42 (m, 5H), 2.50-1.27 (m, 16H) .

Example 3: Preparation of Compound VIIIa

step one:

n-Butyllithium (61 ml, 2.5 M in hexane) was added dropwise to a solution of Compound Xa (39 g) in anhydrous tetrahydrofuran (150 ml). After stirring at -78 ° C for 1 hour, a solution of compound IXa (30 g, mp.: J. Am. Chem. Soc. 1985, 107, 1421.) in anhydrous tetrahydrofuran (100 ml) was added dropwise. After stirring at -78 ° C for 1 hour, it was quenched with water, ethyl acetate and water layer were added and the organic phase was collected. The organic phase was concentrated, and the compound XIVa (53.0 g, yield 91%) was obtained by column chromatography.

XIVa: ¹ H NMR (400MHz, CDCl ₃ ) δ 7.46-7.16 (m, 7H), 6.91 (d, J = 8.2 Hz, 1H), 6.05-5.95 (m, 1H), 5.87-5.71 (m, 1H) , 5.64 (s, 1H), 5.08 (s, 2H), 5.05-4.89 (m, 4H), 4.70-4.60 (m, 1H), 3.90-3.42 (m, 5H), 2.50-1.27 (m, 16H) .

Step two:

Pyridine chlorochromate (40 g) was added to a solution of compound XIVa (45.4 g) in anhydrous dichloromethane (200 mL). The reaction mixture was slowly warmed to 20 ° C and stirred for 2 hours. The reaction mixture was filtered through celite. The filtrate was concentrated, and the compound XVa (38.3 g, yield: 85%) was obtained by column chromatography.

XVa: ¹ H NMR (400MHz, CDCl ₃ ) δ 7.72 (dd, J = 11.3, 7.8 Hz, 1H), 7.45-7.26 (m, 5H), 7.22 (d, J = 7.5 Hz, 1H), 7.07 (dd , J = 8.0, 1.9 Hz, 1H), 6.06-5.90 (m, 1H), 5.80-5.70 (m, 1H), 5.08 (s, 2H), 5.03-4.87 (m, 4H), 4.65-4.55 (m , 1H), 3.95-3.78 (m, 3H), 3.76-3.66 (m, 1H), 3.52-3.38 (m, 1H), 2.60-1.26 (m, 16H).

Step three:

Compound XVa (24.3 g) was dissolved in anhydrous tetrahydrofuran (250 ml), and (R)-2-methyl-CBS-oxazol borane (55 ml, 1 M in toluene) was added dropwise at 0 °C. The reaction mixture was cooled to -30 ° C and borane-dimethyl sulfide complex (30 mL, 2M THF) was then applied. After stirring at -30 ° C for 1 hour, it was quenched by the addition of methanol. The organic phase was collected by adding a 5% aqueous ammonium chloride solution and ethyl acetate. The organic phase was concentrated and purified by column chromatography to afford compound VIIIa (24.5 g, 99%).

VIIIa: ¹ H NMR (400MHz, CDCl ₃ ) δ 7.46-7.16 (m, 7H), 6.91 (d, J = 8.2 Hz, 1H), 6.05-5.95 (m, 1H), 5.87-5.71 (m, 1H) , 5.64 (s, 1H), 5.08 (s, 2H), 5.05-4.89 (m, 4H), 4.70-4.60 (m, 1H), 3.90-3.42 (m, 5H), 2.50-1.27 (m, 16H) .

Example 4: Preparation of Compound VIIa

Compound VIIIa (24.4 g) was dissolved in anhydrous dichloromethane (100 mL). Third butyl dimethyl chlorodecane (11.3 g) and imidazole (8.5 g) were sequentially added at 20 °C. The reaction mixture was stirred at 20 ° C for 2 hours and then quenched with ice water. The solution was separated and the dichloromethane phase was collected. The organic phase was concentrated and purified by column chromatography to afford compound VIIa (25.1 g, yield: 83%).

VIIa: ¹ H NMR (400MHz, CDCl ₃ ) δ 7.44 (d, J = 7.5 Hz, 2H), 7.39 (t, J = 7.4 Hz, 2H), 7.35-7.27 (m, 2H), 7.20 (t, J = 8.0 Hz, 1H), 6.87 (d, J = 8.1 Hz, 1H), 6.05-5.91 (m, 1H), 5.85-5.72 (m 1H), 5.61 (s, 1H), 5.07 (s, 2H), 5.04-4.90 (m, 4H), 4.65-4.55 (m, 1H), 3.90-3.39 (m, 5H), 2.35-1.35 (m, 16H), 0.93 (s, 9H), 0.12 (d, J =11.9) Hz, 6H).

Example 5: Preparation of Compound VIa

Compound VIIa (25.1 g) was dissolved in anhydrous dichloromethane (80 ml) at 20 ° C under nitrogen and then hexanes hexane (15.6 g). After stirring at 20 ° C for 1 hour, the dichloromethane was concentrated to remove. The crude material was dissolved in dry EtOAc (EtOAc) (EtOAc) The reaction mixture was cooled to 20 ° C and concentrated. The crude product was isolated by column chromatography to give compound VIa (26.0 g, yield 99%).

VIa: ¹ H NMR (400MHz, CDCl ₃ ) δ 7.44-7.16 (m, 6H), 6.95 (d, J = 7.2 Hz, 1H), 6.85 (d, J = 7.6 Hz, 1H), 5.85-5.69 (m) , 1H), 5.60-5.45 (m, 1H), 5.06 (s, 2H), 5.01-4.87 (m, 2H), 4.56-4.48 (m, 1H), 3.90-3.30 (m, 5H), 2.69 (dd , J = 18.8, 6.3 Hz, 1H), 2.50-1.25 (m, 18H), 0.82 (s, 9H), 0.13 (m, 6H).

Example 6: Preparation of Compound VIa

A mixture of compound VIIa (2.9 g), palladium chloride (0.1 g), tetramethylthiourea (0.1 g) and lithium chloride (0.2 g) in tetrahydrofuran was reacted with carbon monoxide at 60 ° C for 60 hours. The mixture was cooled to 20 ° C, quenched with water and extracted with ethyl acetate. The organic phase was concentrated, and the compound VIa (2.5 g, yield: 85%) was obtained by column chromatography.

VIa: ¹ H NMR (400MHz, CDCl ₃ ) δ 7.44-7.16 (m, 6H), 6.95 (d, J = 7.2 Hz, 1H), 6.85 (d, J = 7.6 Hz, 1H), 5.85-5.69 (m) , 1H), 5.60-5.45 (m, 1H), 5.06 (s, 2H), 5.01-4.87 (m, 2H), 4.56-4.48 (m, 1H), 3.90-3.30 (m, 5H), 2.69 (dd , J = 18.8, 6.3 Hz, 1H), 2.50-1.25 (m, 18 H), 0.82 (s, 9H), 0.13 (m, 6H).

Example 7: Preparation of Compound I (Precursor Neil)

step one:

To a solution of the compound VIa (26 g) in ethanol (170 ml), anhydrous potassium carbonate (1.3 g) and 10% palladium carbon (6.5 g) were sequentially added at 20 °C. The reaction mixture was hydrogenated at 60 psi hydrogen pressure and 20 ° C for 15 hours. The reaction mixture was filtered through celite. The ethanol filtrate was concentrated to 120 ml to give a compound Va ethanol solution, which was used in the next reaction without purification.

Step two:

Under a nitrogen atmosphere, the ethanol solution of the above compound Va was cooled to -10 ° C, sodium borohydride (1.55 g) was added, and stirring was continued at -10 ° C for 3 hours. The reaction was completed, quenched with aq. aq. The organic phase was collected and the organic phase was concentrated to give crude crude product IVa.

Step three:

Under a nitrogen atmosphere, the methanol solution of the above compound IVa was cooled to 0 ° C, and p-toluenesulfonic acid (780 mg) was added. The reaction mixture was warmed to 20 ° C and stirred for 2 hours. The reaction was completed, quenched with saturated aqueous sodium The organic phase was collected, the organic phase was concentrated, and then crystallised from toluene to afford white solid IIIa (10.5 g, 3 step yield 75%).

IIIa: ¹ H NMR (400 MHz, CD ₃ OD) δ 6.90 (t, J = 7.7 Hz, IH), 6.62 (d, J = 7.9 Hz, 2H), 3.61 (td, J = 9.9, 6.2 Hz, 1H) , 3.52 (s, 1H), 2.73-2.42 (m, 4H), 2.30-2.20 (m, 1H), 2.11-2.01 (m, 1H), 1.99-1.84 (m, 1H), 1.77-1.23 (m, 13H), 1.23-1.14 (m, 1H), 1.14-1.02 (m, 1H), 0.91 (t, J = 6.6 Hz, 3H); ¹³ C NMR (100 MHz, CD ₃ OD) δ 155.2, 141.9, 127.0, 126.1, 120.5, 113.9, 77.7, 73.0, 52.7, 42.4, 42.0, 38.3, 36.1, 34.6, 34.2, 33.2, 29.6, 26.6, 26.5, 23.7, 14.4.

Step four:

Compound IIIa (3 g) was dissolved in acetone under nitrogen, and then chloroacetonitrile (5.8 ml), tetrabutylammonium bromide (290 mg) and potassium carbonate (12.4 g) were added. The reaction mixture was heated to 70 ° C and reacted at 70 ° C for 14 hours. After completion of the reaction, the reaction mixture was cooled to 20 ° C, filtered over Celite, and concentrated. After column chromatography, Compound IIa (3.6 g, 99%) was obtained.

IIa: ¹ H NMR (400MHz, CDCl ₃ ) δ 7.14 (t, J = 7.8 Hz, 1H), 6.90 (d, J = 7.4 Hz, 1H), 6.82 (d, J = 8.2 Hz, 1H), 4.75 ( s, 2H), 3.80-3.70 (m, 1H), 3.80-3.70 (m, 1H), 2.84-2.69 (m, 2H), 2.56-2.44 (m, 2H), 2.31-1.20 (m, 17H), 0.90 (t, J = 6.7 Hz, 3H).

Step five:

Compound IIa (3.6 g) was dissolved in methanol under nitrogen (80 m) l), slowly add 30% aqueous potassium hydroxide solution. The reaction mixture was heated to 60 ° C, and reacted at 60 ° C for 3 hours, and concentrated under reduced pressure to remove methanol to give a pale brown product. Crystallization from ethanol-water gave a white solid pure product, trepronil (3.0 g, yield 86%).

I: [α] ²⁵ _D + 45.2 (c 10 mg/mL, MeOH); ¹ H NMR (400 MHz, CD ₃ OD) δ 7.05 (t, J = 7.9 Hz, 1H), 6.79 (d, J = 7.4 Hz, 1H), 6.70 (d, J = 8.3 Hz, 1H), 4.62 (s, 2H), 3.67-3.57 (m, 1H), 3.56-3.46 (m, 1H), 2.80-2.45 (m, 4H), 2.33 -2.23 (m, 1H), 2.13 - 2.02 (m, 1H), 1.97-1.87 (m, 1H), 1.76-1.04 (m, 15H), 0.92 (t, J = 6.7 Hz, 3H); ¹³ C NMR (100MHz, CD ₃ OD) δ 173.0, 156.6, 142.2, 128.7, 127.2, 122.5, 110.9, 77.7, 72.9, 66.7, 52.8, 42.3, 42.0, 38.3, 36.1, 34.6, 34.1, 33.2, 29.6, 26.6, 26.5, 23.7, 14.4.

Since the present invention has been described in terms of its specific embodiments, certain modifications and equivalents are obvious to those skilled in the art and are included within the scope of the invention.

Claims (27)

a compound of the formula (VI), Wherein P ¹ , P ² and P ³ are each independently hydrogen or a hydroxy protecting group. The compound of claim 1, wherein P ¹ is hydrogen, substituted or unsubstituted C _1-10 alkyl, P ² is hydrogen, substituted or unsubstituted C _1-10 alkyl, and P ³ is Hydrogen or -SiR ¹ R ² R ³ , wherein R ¹ , R ² and R ³ are each a C _1-10 linear or branched alkyl group, a C _3-10 cycloalkyl group, or a substituted or unsubstituted C _6-10 aryl. A preparation method of Treprostinil, characterized by comprising the following steps, Compound (VI) is reduced to obtain compound (V), compound (V) is reduced to obtain compound (IV), compound (IV) is deprotected to obtain compound (III), and compound (III) is reacted with chloroacetonitrile to obtain compound ( II), the compound (II) is hydrolyzed to give Treprostinil, wherein P ¹ , P ² and P ^{3 are} as defined in the first or second aspect of the patent application. The preparation method according to claim 3, wherein the compound (VI) is reduced to obtain a compound (V) which is catalytic hydrogenation reduction of palladium carbon. The production method according to claim 3, wherein the reducing agent used for the reduction of the compound (V) to obtain the compound (IV) is sodium borohydride. A process for producing a compound represented by the formula (VI) according to the first aspect of the invention, which comprises the step of obtaining a compound (VI) by a ring closure reaction of the compound (VII), Wherein P ¹ , P ² , and P ^{3 are} as defined in claim 1 or 2. The production method according to claim 6, wherein the compound (VII) is reacted with dicobalt octacarbonyl to obtain the compound (VI), or the compound (VII) is reacted with carbon monoxide under the action of a palladium catalyst to obtain a compound (VI). The preparation method of claim 7, wherein the palladium catalyst is palladium chloride. a compound of the formula (VIII), Wherein P ¹ and P ^{2 are} as defined in claim 1 or 2. A process for the preparation of a compound of the formula (VIII) according to claim 9 of the invention, which comprises reacting a compound (X) with a compound (IX) under the action of a chiral compound and an organozinc compound. The step of compound (VIII), Wherein P ¹ and P ^{2 are} as defined in claim 1 or 2, and the chiral compound is a compound represented by formula XIII. Wherein Ar ¹ and Ar ² are a substituted or unsubstituted aryl group selected from a phenyl group or a naphthyl group, which is optionally 1 to 5 selected from the group consisting of halogen, trifluoromethyl, methoxy, and amine groups. Substituted with a substituent of a cyano group, a nitro group, a phenyl group or a C _1-6 alkyl group; and R is a substituted or unsubstituted C _1-6 alkyl group. A process for producing a compound represented by the formula (VIII) according to claim 10, wherein the aryl group is a phenyl group. A method for producing a compound represented by the formula (VIII) according to claim 10, wherein R is a methyl group. The production method according to claim 10, wherein the organozinc compound is ZnR' ₂ , wherein R' is a substituted or unsubstituted C _1-6 alkyl group. The production method according to claim 13, wherein R' is a methyl group. A method for preparing a compound represented by formula (VIII) according to claim 9 of the patent application, characterized in that it comprises the following steps, 1) Compound (X) is reacted with compound (IX) to obtain compound (XIV), 2) compound (XIV) is oxidized to obtain compound (XV), and 3) compound (XV) is asymmetrically reduced by a chiral reagent to obtain a compound. (VIII); wherein P ¹ and P ^{2 are} as defined in claim 1 or 2. The preparation method according to claim 15, wherein the reaction of the step 1) is carried out under the action of a base. The preparation method according to claim 16, wherein the base of the step 1) is an organolithium compound. The preparation method of claim 17, wherein the base of the step 1) is n-butyllithium. The preparation method according to any one of claims 15 to 18, wherein the chiral reagent in the step 3) is a ( R )-CBS reagent. a compound of the formula (X), Wherein P ^{1 is} as defined in claim 1 or 2. A method for preparing a compound represented by formula (X) according to claim 20, which comprises the following steps, 1) The compound (XVI) is reacted with the compound (XII) to give the compound (XI), and 2) the compound (XI) is obtained by the action of a base to obtain the compound (X), wherein P ^{1 is} as in the first or second aspect of the patent application. Definitions, R ⁴ is -SiR ¹ R ² R ³ , wherein R ¹ , R ² and R ³ are each independently a C _1-10 straight or branched alkyl group, a C _3-10 cycloalkyl group, or a substituted or Unsubstituted C _6-10 aryl. The preparation method according to claim 21, wherein the reaction of the step 1) is carried out under the action of a base. The preparation method according to claim 22, wherein the base of the step 1) is an organolithium compound. The preparation method according to claim 23, wherein the base of the step 1) is n-butyllithium. The production method according to any one of claims 21 to 24, wherein the base in the step 2) is an inorganic base. The preparation method of claim 25, wherein the base in the step 2) is sodium hydroxide. a compound of the formula (XI), Wherein P ¹ and R ^{4 are} as defined in claim 21 of the scope of the patent application.