CN106831680B - Intermediate for preparing treprostinil, preparation method thereof and method for preparing treprostinil by using intermediate - Google Patents

Intermediate for preparing treprostinil, preparation method thereof and method for preparing treprostinil by using intermediate Download PDF

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CN106831680B
CN106831680B CN201611130947.XA CN201611130947A CN106831680B CN 106831680 B CN106831680 B CN 106831680B CN 201611130947 A CN201611130947 A CN 201611130947A CN 106831680 B CN106831680 B CN 106831680B
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张富尧
郭鹏飞
季维
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Tianjin Hengrui Pharmaceutical Co.,Ltd.
Jiangsu Hengrui Medicine Co Ltd
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Abstract

The present invention relates to an intermediate for preparing treprostinil, a preparation method thereof and a method for preparing treprostinil by the same. In particular, the present invention relates to a compound of formula (VI) for use in the preparation of treprostinil (formula (I)), a method for the preparation thereof, and a method for preparing treprostinil by using the compound. The method for preparing treprostinil comprises the following steps: the compound shown in the formula (III) is obtained by reducing the compound shown in the formula (VI) and deprotecting hydroxyl, and the treprostinil shown in the formula (I) is obtained by hydrolyzing the compound shown in the formula (III) after reacting with chloroacetonitrile. The method has simple operation and high synthesis yield, and is suitable for large-scale production.

Description

Intermediate for preparing treprostinil, preparation method thereof and method for preparing treprostinil by using intermediate
The application is a divisional application of Chinese patent application with the application date of 2012, 12 and 20, and is named as an intermediate for preparing treprostinil, a preparation method thereof and a method for preparing the treprostinil by the intermediate, wherein the application date of the intermediate is 201210556734.9.
Technical Field
The present invention relates to an intermediate for preparing treprostinil, a preparation method thereof and a method for preparing treprostinil by the same.
Background
Pulmonary hypertension is a group of clinical pathophysiological syndromes caused by various reasons, wherein the mean pulmonary artery pressure measured by a right heart catheter in a resting state is greater than or equal to 25 mmHg. As a common clinical cardiovascular disease, pulmonary hypertension is caused by vasospasm of pulmonary arterioles, intimal hyperplasia and remodeling, which results in increased pulmonary vascular resistance, which ultimately can lead to right heart failure and even death.
As a targeted medicine for treating pulmonary hypertension, prostacyclin (PGI2) can promote pulmonary vasodilation, inhibit platelet aggregation and thrombosis, stimulate thrombolysis and inhibit pulmonary vascular remodeling, thereby reducing pulmonary arterial pressure and pulmonary vascular resistance and having obvious curative effect on pulmonary hypertension. Epoprostenol (Flolan), which is the major component of the sodium salt of PGI2, was the first prostacyclin-based drug approved by the Food and Drug Administration (FDA) for the treatment of pulmonary hypertension in 2003. However, since PGI2 has a half-life of about 10 minutes at 25 degrees c and pH 7.6, epoprostenol has an effective duration of action in the human circulation of 3-5 minutes, and thus this treatment requires continuous intravenous administration and low temperature photophobic storage prior to infusion. This limits the widespread use of epoprostenol to some extent, while also facilitating the search for PGI2 derivatives with better stability and bioactivity. Considering that hydrolysis of alkenyl ethers in the PGI2 structure in a weak acid environment may be the main cause of instability of PGI2, scientific researchers have sought alternative derivatives that are chemically stable by modifying or altering the alkenyl ethers. By replacing the alkenyl ether with a functional group of a phenolic ether, Treprostinil (chemical structure shown in formula (I)) was found to be a suitable alternative for the treatment of pulmonary hypertension. The treprostinil has good stability, the half-life period in circulation reaches 4 hours, and the treprostinil can be stored for five years at 25 ℃ without decomposition; and the drug does not break down as it passes through the lungs. Meanwhile, treprostinil has good biological activity and has good curative effects on treating pulmonary hypertension, peripheral vascular diseases and ischemic lesions, improving renal function, neuropathic foot ulcer, asthma and even treating cancers. In particular for the treatment of pulmonary hypertension, a new drug, Remodulin, based on the sodium salt of Treprostinil, was approved by the Food and Drug Administration (FDA) in 2004 for marketing.
Figure BDA0001176170010000021
Because treprostinil has a fused ring structure and multiple chiral centers, its synthesis process is complicated. Aristoff et al first reported the synthesis of treprostinil (Tetrahedron Lett.1982,23, 2067-. The compound 1 is obtained through multi-step synthesis, and ketone in the compound 1 is converted into olefin 2 through olefin reaction; the compound 3 is obtained by the hydroboration reaction through attacking from the front side with smaller steric hindrance, and a chiral center on a C ring is constructed at the same time; the Friedel-Crafts reaction closes the loop to construct the B loop, thereby finally successfully synthesizing the main framework of treprostinil. The chiral synthetic route requires 36 steps of reaction, and is long and not favorable for large-scale synthesis.
Figure BDA0001176170010000031
Scheme 1, one of the Aristoff syntheses
Subsequently, Aristoff et al developed an alternative synthesis (J.am. chem. Soc.1985,107,7967-7974) by introducing the A and B rings via the readily available starting material 5 and synthesizing the C ring by the Wadsworth-Emmons-Wittig reaction (scheme 2). Obtaining a compound 6 through the carbonylation of benzyl position of the compound 5; allylating at the adjacent position of the carbonyl group, and then decarbonylating at a benzyl position to obtain a racemic compound 7; oxidation of the olefin to give lactone 8; the Wadsworth-Emmons-Wittig reaction finally forms a C ring (no chirality), and the hydrogenation reaction and the reduction reaction of sodium borohydride under the alkaline condition determine the other two chiral centers on the C ring, so that the main framework of treprostinil is constructed. The synthesis route has fourteen reaction steps, the synthesis is relatively simple, but the obtained racemic treprostinil cannot be synthesized into a large amount of optically pure treprostinil because a proper chiral resolution reagent is not found.
Figure BDA0001176170010000032
Scheme 2, second Aristoff Synthesis
Based on Aristoff synthesis, treprostinil synthesis was reported by Fuchs et al (bioorg.med.chem.lett.1991,1,79-82), and the synthesis strategy was: the C ring was synthesized first, then the A ring was introduced by 1, 4-addition reaction, and the B ring was closed again by 1, 4-addition reaction (as shown in scheme 3). Synthesizing in multiple steps to obtain a chiral compound 13, and introducing an A ring through 1, 4-addition reaction with a copper reagent 12; deprotection to form benzyl chloride 15; closing the ring by the 1, 4-addition reaction again to form a B ring to obtain a compound 16; finally debenzenesulfonyl can successfully build the main framework of treprostinil (cis-trans ratio of 2: 1). The chiral synthetic route is relatively short, but in the reaction process of debenzosulfonyl, the chiral center on the C ring is eliminated, only the cis-trans isomerization ratio of 2:1 can be obtained, and as no economic and effective separation means is found, optically pure treprostinil cannot be synthesized in a large quantity.
Scheme 3 Fuchs Synthesis
Moriarty et al reported a method for the synthesis of treprostinil using the Pauson-Khand cyclization reaction (J.org.chem.2004,69,1890-1902), the synthetic strategy being: the A ring was introduced by readily available starting materials and then both B and C rings were constructed using the Pauson-Khand cyclization reaction (as shown in scheme 4). Constructing a chiral center by CBS asymmetric reduction of compound 18 obtained by multi-step synthesis to obtain a cyclization reaction precursor compound 19; b ring and C ring are obtained by Pauson-Khand cyclization reaction, and another chiral center on the C ring is constructed under the action of the existing chiral center; hydrogenation reduction removes the chiral control group of the benzyl position, and simultaneously reduces the unsaturated ketene to obtain a cis-form compound 21 (positive and negative isomerization of the ortho-position 4:1 of the carbonyl group); the reduction reaction of sodium borohydride under alkaline condition can reduce carbonyl and determine the ortho chiral center, so as to obtain the main framework of treprostinil. The chiral synthetic route has good manual control, but needs to use excessive expensive chiral CBS reagent and octacarbonyl cobaltous, and has higher synthetic cost.
Figure BDA0001176170010000051
Scheme 4, Moriarty Synthesis
Due to the medical importance of treprostinil and the complexity of the synthesis of treprostinil molecules, there is an urgent need to develop more efficient methods suitable for large-scale production.
Disclosure of Invention
The invention provides a compound shown as a formula (VI), which can be used for preparing treprostinil,
Figure BDA0001176170010000052
wherein, P1，P2And P3Each independently is hydrogen or a hydroxy protecting group; preferably P1Is hydrogen, substituted or unsubstituted C1-10Alkyl radical, P2Is hydrogen, substituted or unsubstituted C1-10Alkyl radical, P3Is hydrogen or-SiR1R2R3Wherein R is1、R2And R3Are each independently C1-10Straight or branched alkyl of (2), C3-10Cycloalkyl of (2), or substituted or unsubstituted C6-10And (4) an aryl group.
In another aspect, the present invention provides a process for the preparation of compound (VI) which can be carried out by the following synthetic route,
Figure BDA0001176170010000061
wherein, P1，P2And P3Each independently is hydrogen or a hydroxy protecting group; preferably P1Is hydrogen, substituted orUnsubstituted C1-10Alkyl radical, P2Is hydrogen, substituted or unsubstituted C1-10Alkyl radical, P3Is hydrogen or-SiR1R2R3Wherein R is1、R2And R3Are each independently C1-10Straight or branched alkyl of (2), C3-10Cycloalkyl of (2), or substituted or unsubstituted C6-10And (4) an aryl group.
The compound (VI) can be prepared by reacting the compound (VII) with octacarbonyldicobalt (Co)2(CO)8) The reaction yielded (Pauson-Khand reaction, ref: chem.2004,69,1890, org.chem.2004); the compound (VII) can also be obtained by reacting with carbon monoxide under the catalysis of palladium chloride (palladium-catalyzed Pauson-Khand reaction, reference: J.Org.chem.2009,74,1657), and the use of palladium-catalyzed Pauson-Khand reaction can avoid the use of expensive dangerous reagent cobalt octacarbonyl, thereby ensuring safer synthetic process and reducing synthetic cost.
In a preferred embodiment of the invention, in the formulae (VI) and (VII), P1Preferably THP, P2Preferably benzyl, P3Is TBS.
The invention also provides a novel method for synthesizing treprostinil by taking the compound (VI) as the initial raw material, namely, the compound (VI) is subjected to palladium-carbon catalytic hydrogenation reduction to obtain a compound (V), the compound (V) is subjected to sodium borohydride reduction and protective group removal to obtain a compound (III), the compound (III) reacts with chloroacetonitrile and then is hydrolyzed to prepare treprostinil,
Figure BDA0001176170010000071
wherein, P1，P2And P3Each independently is hydrogen or a hydroxy protecting group; preferably P1Is hydrogen, substituted or unsubstituted C1-10Alkyl radical, P2Is hydrogen, substituted or unsubstituted C1-10Alkyl radical, P3Is hydrogen or-SiR1R2R3Wherein R is1、R2And R3Are each independently C1-10Straight or branched alkyl of (2), C3-10Cycloalkyl of (2), or substituted or unsubstituted C6-10And (4) an aryl group.
The compound (VII) is obtained by protecting hydroxyl of the compound (VIII),
Figure BDA0001176170010000072
wherein, P1、P2Each independently is hydrogen or a hydroxy protecting group; preferably P1Is hydrogen, substituted or unsubstituted C1-10Alkyl radical, P2Is hydrogen, substituted or unsubstituted C1-10An alkyl group.
The invention also provides a compound shown in the formula (VIII) and a preparation method thereof, the compound shown in the formula (VIII) can be used for preparing treprostinil,
Figure BDA0001176170010000073
wherein, P1、P2Each independently is hydrogen or a hydroxy protecting group; preferably P1Is hydrogen, substituted or unsubstituted C1-10Alkyl radical, P2Is hydrogen, substituted or unsubstituted C1-10An alkyl group.
In the preparation method of the compound (VIII) provided by the present invention, the following method may be employed: the compound (VIII) is obtained by the reaction of the compound (IX) and the compound (X) under the action of a chiral compound and an organic zinc compound,
Figure BDA0001176170010000081
wherein, P1、P2Each independently is hydrogen or a hydroxy protecting group; preferably P1Is hydrogen, substituted or unsubstituted C1-10Alkyl radical, P2Is hydrogen, substituted or unsubstituted C1-10An alkyl group.
The organic zinc compound is ZnR'2Wherein R' is substituted or unsubstituted C1-6Alkyl, preferably methyl.
The chiral compound is a compound shown in a formula XIII,
Figure BDA0001176170010000082
wherein Ar is1And Ar2Is a substituted or unsubstituted aryl group selected from phenyl or naphthyl, optionally substituted by 1 to 5 substituents selected from halogen, trifluoromethyl, methoxy, amino, cyano, nitro, phenyl or C1-6Alkyl substituent substitution; r is substituted or unsubstituted C1-6Alkyl, preferably R is methyl.
In a preferred embodiment of the invention, in the formulae (X) and (VIII), P1Is THP; in formulae (X) and (VIII), P2Is benzyl; in the formula XIII, Ar1And Ar2Is phenyl, R is methyl, and the organic zinc reagent is dimethyl zinc.
Compound (IX) can be synthesized by reference to the literature: am chem soc 1985,107, 1421.
Compound XIII can be synthesized by reference to the literature: tetrahedron: asymmetry 2005, 16, 1953.
By this method, chiral intermediate (VIII) can be obtained from the compound (IX) and (X) by one-step synthesis, so that the multistep reaction (i.e., addition, oxidation and then CBS asymmetric reduction) in the Moritary synthesis method can be avoided, and the use of expensive CBS reagent can be avoided. Therefore, the method improves the synthesis efficiency and reduces the synthesis cost.
The compound (VIII) can also be synthesized by the following method,
Figure BDA0001176170010000091
the method comprises the following steps:
1) reacting the compound (X) with a compound (IX) under the action of alkali to obtain a compound (XIV),
2) oxidizing the compound (XIV) to obtain a compound (XV),
3) and (3) carrying out asymmetric reduction on the compound (XV) under the action of a chiral reagent to obtain a compound (VIII).
The alkali in the step 1) is an organic lithium compound, preferably n-butyllithium; the oxidation reaction in the step 2) can be Swern oxidation or oxidation by pyridinium chlorochromate; the chiral reagent in the step 3) is a (R) -CBS reagent.
The use of CBS reagents to control asymmetric reduction is a common method for reducing ketones to chiral alcohols, as can be seen in the literature: J.am.chem.Soc.1987,109, 5551.
The invention also provides a compound shown in the formula (X) and a preparation method thereof, the compound shown in the formula (X) can be used for preparing treprostinil,
Figure BDA0001176170010000092
wherein, P1Is hydrogen or a hydroxy protecting group, preferably P1Is hydrogen, substituted or unsubstituted C1-10An alkyl group.
The compound (X) can be prepared by the following synthetic method,
Figure BDA0001176170010000093
wherein, P1Is hydrogen or a hydroxy protecting group, preferably P1Is hydrogen, substituted or unsubstituted C1-10An alkyl group; r4is-SiR1R2R3Wherein R is1、R2And R3Are each independently C1-10Straight or branched alkyl of (2), C3-10Cycloalkyl, substituted or unsubstituted C6-10And (4) an aryl group.
The method comprises the following steps:
1) the compound (XVI) reacts with the compound (XII) under the action of alkali to obtain a compound (XI),
2) the compound (XI) is subjected to the action of alkali to obtain a compound (X).
The alkali in the step 1) is an organic lithium compound, preferably n-butyllithium; the alkali in the step 2) is inorganic alkali, preferably sodium hydroxide.
Compound (XII) can be synthesized by reference to the literature: tetrahedron, 2010, 66, 2351.
The invention also provides a compound shown as a formula (XI),
wherein, P1And R4As defined for compound (X).
The preparation method of treprostinil provided by the invention has the characteristics of safe operation, high synthesis efficiency, low synthesis cost, suitability for industrial production and the like, and has remarkable social and economic benefits.
The terms used in the present invention have the following meanings, unless otherwise stated:
"alkyl" refers to a saturated aliphatic hydrocarbon group, including 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, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2, 3-dimethylbutyl, and the like. Alkyl groups may be substituted or unsubstituted, and when substituted, the substituents may be substituted at any available point of attachment, preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo.
"cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent comprising from 3 to 10 carbon atoms, preferably C3-8Cycloalkyl radicals, morePreferably C3-6Cycloalkyl, most preferably 5 or 6 membered cycloalkyl. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like. Polycyclic cycloalkyl groups include spiro, fused and bridged cycloalkyl groups. Cycloalkyl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkoxy, halogen, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl.
"aryl" refers to a 6 to 14 membered all carbon monocyclic or fused polycyclic (i.e., rings which share adjacent pairs of carbon atoms) group having a conjugated pi-electron system, preferably 6 to 10 membered, more preferably phenyl and naphthyl. The aryl group may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio.
"hydroxyl-protecting Groups" are suitable Groups known in the art for hydroxyl protection, see the literature ("Protective Groups in Organic Synthesis", 5)ThEd.T.W.Greene&P.g.m.wuts). By way of example, the hydroxyl protecting group may preferably be (C)1-10Alkyl or aryl)3Silane groups, for example: triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl and the like; may be C1-10Alkyl or substituted alkyl, for example: methyl, t-butyl, allyl, benzyl, methoxymethyl, ethoxyethyl, 2-Tetrahydropyranyl (THP), etc.; may be (C)1-10Alkyl or aryl) acyl groups, such as: formyl, acetyl, benzoyl and the like; may be (C)1-6Alkyl or C6-10Aryl) sulfonyl; or (C)1-6Alkoxy or C6-10Aryloxy) carbonyl.
Abbreviation table:
abbreviations Full scale
Bn Benzyl radical
DHP 3, 4-dihydro (2H) pyrans
TBS Tert-butyldimethylsilyl group
THP 2-tetrahydropyranyl group
Detailed Description
The present invention will be described in detail below with reference to specific examples to enable those skilled in the art to more fully understand the present invention, wherein the specific examples are provided only for illustrating the technical solutions of the present invention and are not intended to limit the present invention in any way.
The following table shows the structural formulae of the compounds mentioned in the examples
Figure BDA0001176170010000111
Figure BDA0001176170010000121
Example 1: preparation of Compound Xa
To a solution of 1- (trimethylsilyl) propyne (XVIa, from Shanghai Rui-pharmaceutical science and technology, Inc.) (74 g) in anhydrous tetrahydrofuran (200 ml) was added dropwise n-butyllithium (250 ml, 2.5M hexane solution) at 0 ℃ under nitrogen. After stirring at 0 ℃ for 3 hours, a solution of compound XIIa (65.8 g, reference: Tetrahedron 2010, 66, 2351) in anhydrous tetrahydrofuran (100 ml) was added dropwise, and the reaction mixture was slowly warmed to 20 ℃ and stirred at 20 ℃ for 12 hours. The reaction was quenched with saturated aqueous ammonium chloride, ethyl acetate and water were added to separate layers, and the organic phase was collected. The organic phase was concentrated to give crude XIa as a yellow oil, which was used directly for the next reaction without purification.
Sodium hydroxide (39.2 g) was slowly added to the ethanol solution of crude XIa at 20 ℃ under nitrogen. After stirring at 20 ℃ for 12 hours, the reaction mixture was concentrated. Compound Xa (59 g, 88% over two steps) was isolated by column chromatography.
Xa：1H NMR(400MHz,CDCl3)δ5.80(ddd,J＝17.1,10.1,6.9Hz,1H),4.98(dd,J＝22.2,13.1Hz,2H),4.65(dd,J＝6.9,4.0Hz,1H),3.90(dd,J＝10.7,6.2Hz,1H),3.73(dd,J＝10.3,4.3Hz,1H),3.50(dd,J＝11.0,5.6Hz,1H),2.33(dt,J＝7.5,4.0Hz,1H),2.24(td,J＝7.3,2.5Hz,1H),2.05(dd,J＝13.5,6.8Hz,2H),1.93(dt,J＝5.3,2.6Hz,1H),1.82-1.30(m,12H)。
Example 2 preparation of Compound VIIIa
A toluene solution of dimethylzinc (200 ml, 1.0M) was added to a toluene solution of Compound Xa (47.3 g) at 20 deg.C under nitrogen, followed by a toluene solution of Compound XIIIa (3.80 g, see literature: Tetrahedron: Asymmetry 2005, 16, 1953). The mixture was cooled to-10 ℃ and a solution of compound IXa (12.6 g, ref: J.Am.chem.Soc.1985,107, 1421) in toluene was added dropwise. After stirring at-10 ℃ for 6 hours, the reaction was quenched with saturated aqueous ammonium chloride, and ethyl acetate and water were added to separate layers and the organic phase was collected. The organic phase was concentrated and isolated by column chromatography to give compound VIIIa (23.2 g, yield 95%).
VIIIa：1H NMR(400MHz,CDCl3)δ7.46-7.16(m,7H),6.91(d,J＝8.2Hz,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
The method comprises the following steps:
to a solution of compound Xa (39 g) in dry tetrahydrofuran (150 ml) was added dropwise n-butyllithium (61 ml, 2.5M in hexane) at-78 ℃ under nitrogen. After stirring at-78 ℃ for 1 hour, a solution of compound IXa (30 g, ref: J.Am.chem.Soc.1985,107, 1421.) in dry tetrahydrofuran (100 ml) was added dropwise. After stirring at-78 ℃ for 1 hour, quench with water, add ethyl acetate and separate the aqueous layer and collect the organic phase. The organic phase was concentrated and isolated by column chromatography to give compound XIVa (53.0 g, 91% yield).
XIVa：1H NMR(400MHz,CDCl3)δ7.46-7.16(m,7H),6.91(d,J＝8.2Hz,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:
to a solution of compound XIVa (45.4 g) in dry dichloromethane (200 ml) was added pyridinium chlorochromate (40 g) at 0 ℃ under nitrogen. The reaction mixture was slowly warmed to 20 ℃ and stirred for 2 hours. The reaction mixture was filtered through celite. The filtrate was concentrated and isolated by column chromatography to give compound XVa (38.3 g, yield 85%).
XVa：1H NMR(400MHz,CDCl3)δ7.72(dd,J＝11.3,7.8Hz,1H),7.45-7.26(m,5H),7.22(d,J＝7.5Hz,1H),7.07(dd,J＝8.0,1.9Hz,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) under nitrogen and (R) -2-methyl-CBS-oxazaborolidine (55 ml, 1M in toluene) was added dropwise at 0 ℃. The reaction mixture was cooled to-30 ℃ and borane-dimethyl sulfide complex (30 ml, 2M tetrahydrofuran solution) was added. After stirring at-30 ℃ for 1 hour, add methanol to quench. 5% aqueous ammonium chloride and ethyl acetate were added and the organic phase was collected. The organic phase is concentrated and isolated by column chromatography to give compound VIIIa (24.5 g, 99%).
VIIIa：1H NMR(400MHz,CDCl3)δ7.46-7.16(m,7H),6.91(d,J＝8.2Hz,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) under nitrogen. T-butyldimethylsilyl chloride (11.3 g) and imidazole (8.5 g) were added successively at 20 ℃. The reaction mixture was stirred at 20 ℃ for 2 hours and then quenched with ice water. The dichloromethane phase was collected after the solution was partitioned. The organic phase was concentrated and isolated by column chromatography to give compound VIIa (25.1 g, 83% yield).
VIIa：1H NMR(400MHz,CDCl3)δ7.44(d,J＝7.5Hz,2H),7.39(t,J＝7.4Hz,2H),7.35-7.27(m,2H),7.20(t,J＝8.0Hz,1H),6.87(d,J＝8.1Hz,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＝11.9Hz,6H)。
Example 5 preparation of Compound VIa
Compound VIIa (25.1 g) was dissolved in anhydrous dichloromethane (80 ml) at 20 ℃ under nitrogen protection, followed by the addition of dicobalt octacarbonyl (15.6 g). After stirring at 20 ℃ for 1 hour, dichloromethane was removed by concentration. The crude product was dissolved in anhydrous acetonitrile (80 ml) and the reaction mixture was heated to reflux and stirred under nitrogen for 2 hours. The reaction mixture was cooled to 20 ℃ and concentrated. The crude product was isolated by column chromatography to give compound VIa (26.0 g, 99% yield).
VIa：1H NMR(400MHz,CDCl3)δ7.44-7.16(m,6H),6.95(d,J＝7.2Hz,1H),6.85(d,J＝7.6Hz,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＝18.8,6.3Hz,1H),2.50-1.25(m,18H),0.82(s,9H),0.13(m,6H)。
Example 6 preparation of Compound VIa
A tetrahydrofuran mixture of compound VIIa (2.9 g), palladium chloride (0.1 g), tetramethylthiourea (0.1 g) and lithium chloride (0.2 g) was reacted with carbon monoxide at 60 ℃ for 60 hours. Cooling the mixture to 20 ℃, adding water to quench the reaction, adding ethyl acetate to extract, and collecting an organic phase. The organic phase was concentrated and isolated by column chromatography to give compound VIa (2.5 g, 85% yield).
VIa：1H NMR(400MHz,CDCl3)δ7.44-7.16(m,6H),6.95(d,J＝7.2Hz,1H),6.85(d,J＝7.6Hz,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＝18.8,6.3Hz,1H),2.50-1.25(m,18H),0.82(s,9H),0.13(m,6H)。
EXAMPLE 7 preparation of Compound I (Treprostinil)
The method comprises the following steps:
to a solution of compound VIa (26 g) in ethanol (170 ml) at 20 ℃, anhydrous potassium carbonate (1.3 g) and 10% palladium on carbon (6.5 g) were added in this order. The reaction mixture was hydrogenated at 60psi hydrogen pressure and 20 ℃ for 15 hours. The reaction mixture was filtered through celite. The ethanol filtrate was concentrated to 120 ml to obtain an ethanol solution of compound Va, which was used in the next reaction without purification.
Step two:
under the protection of nitrogen, the ethanol solution of the compound Va is cooled to-10 ℃, sodium borohydride (1.55 g) is added, and the mixture is continuously stirred for 3 hours at-10 ℃. After the reaction, the mixture was quenched with a saturated aqueous ammonium chloride solution, and dichloromethane was added to separate layers. The organic phase was collected and concentrated to give crude IVa as a yellow oil which was taken directly to the next step after dissolving in methanol.
Step three:
under nitrogen, the methanol solution of compound IVa was cooled to 0 ℃ and p-toluenesulfonic acid (780 mg) was added. The reaction mixture was warmed to 20 ℃ and stirred for 2 hours. After the reaction, adding saturated sodium bicarbonate aqueous solution for quenching, and adding dichloromethane for layering. The organic phase was collected, concentrated and recrystallized from toluene to yield IIIa as a white solid (10.5 g, 75% over 3 steps).
IIIa：1H NMR(400MHz,CD3OD)δ6.90(t,J＝7.7Hz,1H),6.62(d,J＝7.9Hz,2H),3.61(td,J＝9.9,6.2Hz,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＝6.6Hz,3H)；13C NMR(100MHz,CD3OD)δ155.2,141.9,127.0,126.1,120.5,113.9,77.7,73.0,52.7,42.4,42.0,38.3,36.1,34.6,34.2,33.2,29.6,26.6,26.5,23.7,14.4。
Step four:
compound IIIa (3 g) was dissolved in acetone under nitrogen and chloroacetonitrile (5.8 ml), tetrabutylammonium bromide (290 mg) and potassium carbonate (12.4 g) were added sequentially. The reaction mixture was heated to 70 ℃ and reacted at 70 ℃ for 14 hours. After the reaction was completed, the reaction mixture was cooled to 20 ℃, filtered through celite, and the filtrate was concentrated. After column chromatography, compound IIa (3.6 g, 99%) was obtained.
IIa：1H NMR(400MHz,CDCl3)δ7.14(t,J＝7.8Hz,1H),6.90(d,J＝7.4Hz,1H),6.82(d,J＝8.2Hz,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＝6.7Hz,3H)。
Step five:
compound IIa (3.6 g) was dissolved in methanol (80 ml) under nitrogen and 30% aqueous potassium hydroxide was added slowly. The reaction mixture was heated to 60 ℃ and reacted at 60 ℃ for 3 hours, and the methanol was removed by concentration under reduced pressure to give a light brown crude product. Crystallization from ethanol-water gave the pure product treprostinil as a white solid (3.0 g, 86% yield).
I：[α]25 D+45.2(c 10mg/mL,MeOH)；1H NMR(400MHz,CD3OD)δ7.05(t,J＝7.9Hz,1H),6.79(d,J＝7.4Hz,1H),6.70(d,J＝8.3Hz,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＝6.7Hz,3H)；13C NMR(100MHz,CD3OD)δ173.0,156.6,142.2,128.7,127.2,122.5,110.9,77.7,72.9,66.7,52.8,42.3,42.0,38.3,36.1,34.6,34.1,33.2,29.6,26.6,26.5,23.7,14.4。
Since the invention has been described in terms of specific embodiments thereof, certain modifications and equivalent variations will be apparent to those skilled in the art and are intended to be included within the scope of the invention.

Claims (9)

1. A process for the preparation of a compound of formula (VIII),
Figure FDA0002157286580000011
characterized by comprising the step of reacting a compound (X) with a compound (IX) under the action of a chiral compound and an organozinc compound to obtain a compound (VIII),
Figure FDA0002157286580000012
wherein, P1、P2Each independently is a hydroxyl protecting group, the chiral compound is a compound shown as a formula XIII,
Figure FDA0002157286580000013
wherein Ar is1And Ar2Is a substituted or unsubstituted aryl group selected from phenyl or naphthyl, optionally substituted by 1 to 5 substituents selected from halogen, trifluoromethyl, methoxy, amino, cyano, nitro, phenyl or C1-6Alkyl substituent substitution; r is substituted or unsubstituted C1-6An alkyl group.
2. The method of claim 1, wherein said Ar is selected from the group consisting of1And Ar2Is selected from phenyl; r is methyl.
3. Preparation process according to claim 1 or 2, characterized in that the organozinc compound is ZnR'2Wherein R' is substituted or unsubstituted C1-6An alkyl group.
4. The process according to claim 3, characterized in that R' is methyl.
5. A preparation method of treprostinil comprises the following steps,
Figure FDA0002157286580000021
reducing the compound (VI) to obtain a compound (V), reducing the compound (V) to obtain a compound (IV), removing a protecting group from the compound (IV) to obtain a compound III, reacting the compound III with chloroacetonitrile to obtain a compound II, and hydrolyzing the compound II to obtain treprostinil;
a step of obtaining a compound (VI) by a ring-closing reaction of the compound (VII),
Figure FDA0002157286580000022
and a step of obtaining a compound (VII) by hydroxyl group protection of the compound (VIII),
Figure FDA0002157286580000023
characterized in that the compound shown in the formula (VIII) is obtained by reacting a compound (X) with a compound (IX) under the action of a chiral compound and an organic zinc compound,
Figure FDA0002157286580000024
wherein the chiral compound is shown as a formula XIII,
Figure FDA0002157286580000031
wherein, P1，P2As defined in claim 1, P3is-SiR1R2R3Wherein R is1、R2And R3Are each independently C1-10Straight or branched alkyl of (2), C3-10Cycloalkyl of (2), or substituted or unsubstituted C6-10Aryl radical, Ar1And Ar2Is a substituted or unsubstituted aryl group selected from phenyl or naphthyl, optionally substituted by 1 to 5 substituents selected from halogen, trifluoromethyl, methoxy, amino, cyano, nitro, phenyl or C1-6Alkyl substituent substitution; r is substituted or unsubstituted C1-6An alkyl group.
6. The method according to claim 5, wherein Ar is Ar1And Ar2Is phenyl; r is methyl.
7. Preparation process according to claim 5 or 6, characterized in that the organozinc compound is ZnR'2Wherein R' is substituted or unsubstituted C1-6An alkyl group.
8. The process according to claim 7, wherein R' is methyl.
9. The process according to claim 5, wherein the compound represented by the formula (X) is produced by a process comprising,
Figure FDA0002157286580000032
1) the compound (XVI) reacts with the compound (XII) to obtain a compound (XI),
2) the compound (XI) is subjected to the action of alkali to obtain a compound (X),
wherein, P1As defined in claim 5, R4is-SiR1R2R3Wherein R is1、R2And R3Are each independently C1-10Straight or branched alkyl of (2), C3-10Cycloalkyl of (2), or substituted or unsubstituted C6-10And (4) an aryl group.
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CN1494524A (en) * 2001-01-05 2004-05-05 �Ƹ��� Process for stereo selective synthesis of prostacyclin derivatives
WO2011153363A1 (en) * 2010-06-03 2011-12-08 United Therapeutics Corporation Treprostinil production
WO2012009816A1 (en) * 2010-07-22 2012-01-26 Alphora Research Inc. Synthesis of treprostinil and intermediates useful therein

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US20110294815A1 (en) * 2008-06-27 2011-12-01 Harbeson Scott L Prostacyclin analogs

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1494524A (en) * 2001-01-05 2004-05-05 �Ƹ��� Process for stereo selective synthesis of prostacyclin derivatives
WO2011153363A1 (en) * 2010-06-03 2011-12-08 United Therapeutics Corporation Treprostinil production
WO2012009816A1 (en) * 2010-07-22 2012-01-26 Alphora Research Inc. Synthesis of treprostinil and intermediates useful therein

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
Enantioselective addition of dimethylzinc to aldehydes catalyzed by N-substituted mandelamide-Ti(IV) complexes;Gonzalo Blay et al;《Tetrahedron: Asymmetry》;20050523;第16卷;第1953-1958页 *
The Intramolecular Asymmetric Pauson -Khand Cyclization as a Novel and General Stereoselective Route to Benzindene Prostacyclins: Synthesis of UT-15 (Treprostinil);Robert M. Moriarty et al;《J. Org. Chem.》;20040219;第69卷;第1890-1902页 *

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