A preparation method of iloprost
Through a new Iloprost synthesis route, the steps are simplified and the yield is improved, and the problems of many synthesis steps and low yields in the prior art are solved, thus achieving simplicity of the process and the convenience of industrial production.
Patent Information
- Application Number
- CN202010415896.5
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- Filing Date
- 2020-05-16
- Publication Date
- 2025-06-27
- Estimated Expiration
- 2040-05-16
AI Technical Summary
The existing Iloprost synthesis method has many steps, low overall yield, complex operation, harsh reaction conditions, and harsh side chain segmented connection conditions, resulting in an increase in the length of the synthesis route and a decrease in yield.
A new synthetic route is adopted, including the reaction of the compound of formula II and the compound of formula VII in the presence of base and solvent to obtain the compound of formula III, followed by the Dess-Martin oxidation reaction in the presence of solvent and base, followed by the Wittig-Horner reaction in the presence of base, followed by the reduction reaction in the presence of reducing agent and solvent, and finally deprotection group under acidic conditions to obtain iloprost.
This method reduces the synthesis steps, improves the overall yield, simplifies operations, and moderates the reaction conditions, making the industrial production of Iloprost more convenient.
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Figure CN113683544B_ABST
Abstract
Description
Technical Field
[0001] The present invention belongs to the field of drug synthesis and relates to a preparation method of iloprost. Background Art
[0002] Iloprost, developed by Bayer, with the trade name Ventavis, was approved by the US FDA on December 29, 2004 for the treatment of pulmonary arterial hypertension (PAH), and was approved for marketing in China by the State Food and Drug Administration in 2006. It is one of the four imported targeted drugs currently approved for the treatment of pulmonary arterial hypertension. The chemical name of iloprost is 5-{(E)-(1S,5S,6R,7R)-7-hydroxy-6-[(E)-(3S,4RS)-3-hydroxy-4-methyl-1-octen-6-ynyl]-bicyclo[3.3.0]oct-3-ylidene}-pentanoic acid, and its molecular formula is C 22 H 32 O4, and its structural formula is as follows:
[0003]
[0004] There are many literature reports on the synthesis of iloprost, and basically all are total synthesis routes with more than 20 steps. For example, Gais H J et al. in Chemistry - A European Journal, 2006, 12(21):5610 - 5617 first prepared the chiral bicyclic mother nucleus by resolving the racemate, then introduced the chiral alkynyl side chain in two segments, and finally introduced the pentanoic acid side chain to obtain iloprost.
[0005]
[0006] For another example, Guido J. Kramp et al. in J.AM.CHEM.SOC.2005, 127, 17910 - 17920 first prepared the chiral bicyclic mother nucleus by chiral induction, introduced the chiral alkynyl side chain in one step, and finally introduced the pentanoic acid side chain in two segments to obtain iloprost. This route provides a method for forming the E - type double bond when constructing the pentanoic acid side chain, but the reaction conditions are harsh, requiring a reaction at - 62°C for six days.
[0007]
[0008] The above two types of synthesis methods are mostly linear synthesis routes, which have the disadvantages of long steps, low overall yield, complex operation, harsh reaction conditions and the need to use expensive reagents, etc. Moreover, although the segmented connection of the two side chains can increase the proportion of the required E - type double bond, the conditions are harsh and it further increases the length of the synthesis route, resulting in a further reduction in the yield.
[0009] In patents WO2011003058 and US2009325976, these two side chains were introduced separately through one-step reactions after the chiral mother ring was prepared. However, when introducing the valeric acid side chain, a mixture of E-type / Z-type in a ratio of about 2:1 was obtained, which caused great waste to the chiral mother ring prepared through many steps of reactions.
[0010]
[0011] Therefore, conducting process research on the synthesis of iloprost, optimizing the synthesis route and process operations, reducing steps, increasing the yield, and improving the purity are of great significance for the industrial production of iloprost. Summary of the Invention
[0012] The present invention provides a method for preparing iloprost, which includes the following steps:
[0013] A. The compound of formula II reacts with the compound of formula VII in the presence of a base and a solvent to obtain the compound of formula III.
[0014]
[0015] B. In the presence of a solvent and a base, the compound of formula III undergoes a Dess-Martin oxidation reaction with the Dess-Martin reagent to obtain the compound of formula IV.
[0016]
[0017] C. The compound of formula IV undergoes a Wittig-Horner reaction with the compound of formula VIII in the presence of a base to obtain the compound of formula V.
[0018]
[0019] D. The compound of formula V undergoes a reduction reaction in the presence of a reducing agent and a solvent to obtain the compound of formula VI.
[0020]
[0021] E. Under acidic conditions, the protecting group on the hydroxyl group of the compound of formula VI is removed to obtain the compound of formula I.
[0022]
[0023] Wherein R is one of trimethylsilyl ether, triethylsilyl ether, tert-butyldimethylsilyl ether, tert-butyldiphenylsilyl ether, and triisopropylsilyl ether.
[0024] In some embodiments, the base in step A is one of KHMDS, LiHMDS, and NaHMDS; in some embodiments, the base in step A is KHMDS. In some embodiments, the reaction temperature in step A is 5 to 40 °C.
[0025] In some embodiments, the reaction temperature in step B is -5 to 15 °C; in some embodiments, the reaction temperature in step B is 0 to 10 °C. In some embodiments, the basic reagent in step B is selected from one of sodium bicarbonate and pyridine. In some embodiments, the reaction solvent in step B is one of chloroform, 1,2-dichloroethane, acetonitrile, and dichloromethane; in some embodiments, the reaction solvent in step B is dichloromethane.
[0026] In some embodiments, the basic reagent in step C is selected from one of sodium hydride, n-butyllithium, potassium tert-butoxide, sodium tert-butoxide, KHMDS, and NaHMDS; in some embodiments, the basic reagent in step C is potassium tert-butoxide or sodium tert-butoxide.
[0027] In some embodiments, the reducing agent in step D is selected from one of borane / R-(+)-Me-CBS and sodium borohydride / diethylmethoxyborane. In some embodiments, the reducing agent in step D is borane / R-(+)-Me-CBS. In some embodiments, the reaction temperature in step D is -5 to 30 °C.
[0028] In some embodiments, the acidic reagent in step E is selected from one of p-toluenesulfonic acid and dilute hydrochloric acid. In some embodiments, the acidic reagent in step E is p-toluenesulfonic acid. In some embodiments, the reaction temperature in step E is 10 to 50 °C.
[0029] On the other hand, the present invention provides a compound with the following structural formula:
[0030]
[0031] On the other hand, the use of the compounds of formula III-1, formula IV-1, and formula V-1 in the preparation of iloprost.
[0032] The present invention provides a new synthetic route for iloprost, which has the advantages of fewer reaction steps, simple and easy-to-control process, high total yield, mild reaction conditions, and easy industrial production. Detailed Description of the Invention
[0033] The following are specific examples to further illustrate the present application. It should be understood that these examples are only used to illustrate the present application and do not limit the protection scope of the present application.
[0034] Example 1 Synthesis of the Compound of Formula III-1
[0035]
[0036] Under nitrogen protection, the compound of formula VII (31.2 g, 70.4 mmol) was added to 170 ml of anhydrous tetrahydrofuran. A 1 M KHMDS / THF solution (105.6 ml, 105.6 mmol) was added dropwise at room temperature, and the mixture was stirred for 30 min. The compound of formula II-1 (5.0 g, 17.6 mmol) dissolved in anhydrous tetrahydrofuran was added dropwise, and the mixture was stirred for 24 h. Water (50 ml) was added to the reaction solution to quench the reaction, and 0.5 N dilute hydrochloric acid was added dropwise to adjust the pH to 6 - 7. The layers were separated, and the aqueous layer was extracted with ethyl acetate (50 ml × 3). The organic layers were combined and washed successively with water (50 ml × 3) and saturated brine (50 ml). Dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. After the filtrate was evaporated to dryness, it was purified by column chromatography to obtain a pale yellow oil (3.9 g). The title compound III-1, namely the E-type diastereoisomer, 32.6 g, was obtained by preparative liquid-phase resolution with a yield of 45%.
[0037] MS: 391.5 [M+Na]+. 1 H NMR (400 MHz, DMSO) δ 11.96 (s, 1H), 5.17 (t, J = 7.2 Hz, 1H), 4.36 (s, 1H), 3.86–3.73 (m, 1H), 3.51–3.34 (m, 2H), 2.40–2.33 (m, 1H), 2.27–1.89 (m, 10H), 1.58–1.48 (m, 2H), 1.37–1.28 (m, 1H), 1.15–1.04 (m, 1H), 0.86 (s, 9H), 0.02 (d, J = 3.0 Hz, 6H).
[0038] Example 2 Synthesis of the compound of formula IV-1
[0039]
[0040] Under nitrogen protection, the compound of formula III-1 (2.0 g, 5.4 mmol) was dissolved in 200 ml of anhydrous dichloromethane. The temperature was lowered to 0 °C, Dess-Martin periodinane (11.5 g, 27 mmol) and sodium bicarbonate (6.8 g, 86.4 mmol) were added, and the mixture was stirred for 30 min. Then the temperature was raised to 10 °C and the reaction was carried out for 12 h. Water (10 ml) was added to the system to quench the reaction, and the pH was adjusted to 6 - 7 with saturated aqueous sodium bicarbonate. The layers were separated, and the aqueous layer was extracted with dichloromethane (20 ml × 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered through diatomaceous earth, and the crude product obtained by evaporating the filtrate to dryness was a colorless oil (2 g), which was directly used in the next step of the reaction.
[0041] Example 3 Synthesis of the compound of formula V-1
[0042]
[0043] Under nitrogen protection, potassium tert-butoxide (3.7 g, 32.8 mmol) was added to 75 ml of anhydrous tetrahydrofuran. The compound of Formula VIII (6.34 g, 27.3 mmol) dissolved in 63 ml of anhydrous tetrahydrofuran was added dropwise at room temperature, and the mixture was stirred at 45 °C for 30 min. The reaction system was cooled to room temperature, and the compound of Formula IV-1 (2 g, 5.5 mol) dissolved in 36 ml of anhydrous tetrahydrofuran was added dropwise, and the mixture was stirred at room temperature for 2 h. Water (50 ml) was added to the system to quench the reaction, and the pH was adjusted to 6 - 7 with 0.5 N dilute hydrochloric acid. Liquid separation was performed, and the aqueous phase was extracted with ethyl acetate (20 ml × 3). The combined organic phases were washed successively with saturated aqueous sodium thiosulfate (20 ml × 3), water (20 ml × 3), and saturated brine (20 ml). Dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and purified by column chromatography to obtain a pale yellow oil (1.4 g), with a two-step yield of 54%.
[0044] MS: 495.1 [M+Na]+. 1 H NMR (400 MHz, DMSO) δ 12.02 (s, 1H), 6.85–6.71 (m, 1H), 6.19 (dd, J = 15.7, 6.0 Hz, 1H), 5.23 (t, J = 7.0 Hz, 1H), 3.97–3.84 (m, 1H), 3.04–2.89 (m, 1H), 2.47–1.91 (m, 14H), 1.74–1.66 (m, 3H), 1.59–1.49 (m, 2H), 1.19–1.09 (m, 1H), 1.10–0.97 (m, 3H), 0.80 (s, 9H), -0.03 (d, J = 9.1 Hz, 6H).
[0045] Example 4 Synthesis of the Compound of Formula VI-1
[0046]
[0047] Under nitrogen protection, dissolve 2.0 M borane dimethyl sulfide / THF solution (2.8 ml, 5.50 mmol) in 66 ml of anhydrous dichloromethane. Cool the reaction system to -5 °C, and then add 1.0 M R-(+)-Me-CBS / toluene solution (5.50 ml, 5.50 mmol). Stir for 15 min. Dropwise add the compound of formula V-1 (1.3 g, 2.75 mmol) dissolved in 28 ml of anhydrous dichloromethane, warm up to 10 °C, and stir for 15 min. Quench with 10 ml of water in the reaction solution, separate the layers, extract the aqueous layer with DCM (10 ml × 3), combine the organic phases, wash the organic phases successively with water (10 ml × 3) and saturated brine (10 ml), dry over anhydrous sodium sulfate, filter, evaporate the filtrate to dryness and purify by column chromatography to obtain a colorless oil (1.03 g). The yield is 67%.
[0048] MS: 497.2 [M+Na]+. 1 H NMR (600 MHz, DMSO) δ 5.51–5.45 (m, 1H), 5.40–5.35 (m, 1H), 5.21 (t, J = 7.0 Hz, 1H), 4.64 (s, 1H), 3.92–3.75 (m, 1H), 3.75–3.70 (m, 1H), 2.47–2.40 (m, 1H), 2.33–2.26 (m, 1H), 2.23–1.86 (m, 10H), 1.79–1.74 (m, 1H), 1.73 (s, 3H), 1.58–1.55 (m, 1H), 1.55–1.51 (m, 3H), 1.13–1.06 (m, 1H), 0.87 (t, J = 6.4 Hz, 3H), 0.83 (s, 9H), 0.01– -0.02 (m, 6H).
[0049] Synthesis of Compound I Iloprost in Example 5
[0050]
[0051] Dissolve the compound of formula VI-1 (1.03 g, 2.2 mmol) in 65 ml of acetone and 15 ml of water, add p-toluenesulfonic acid monohydrate (0.42 g, 2.2 mmol), and stir at 30 °C for 12 h. Add saturated sodium bicarbonate aqueous solution (20 ml), and concentrate under reduced pressure to evaporate acetone. Extract the remaining aqueous phase with ethyl acetate (10 ml × 3), combine the organic phases, wash successively with water (10 ml × 3) and saturated brine (10 ml), dry over anhydrous sodium sulfate, filter, evaporate the filtrate to dryness and purify by column chromatography to obtain 0.40 g of a pale yellow oil, which is iloprost, and the yield is 92%.
[0052] MS: 383.1 [M+Na]+. 1¹H NMR (600 MHz, DMSO) δ 11.97 (s, 1H), 5.54–5.41 (m, 1H), 5.39–5.28 (m, 1H), 5.20 (t, J = 7.0 Hz, 1H), 4.67–4.56 (m, 1H), 4.53 (s, 1H), 3.90–3.70 (m, 1H), 3.55 (s, 1H), 2.47–2.39 (m, 1H), 2.30–2.24 (m, 1H), 2.24–2.21 (m, 1H), 2.21–2.17 (m, 2H), 2.17–2.11 (m, 1H), 2.11–2.09 (m, 1H), 2.09–1.99 (m, 2H), 1.99–1.97 (m, 1H), 1.97–1.95 (m, 1H), 1.95–1.93 (m, 1H), 1.92–1.86 (m, 1H), 1.73 (s, 3H), 1.72–1.64 (m, 1H), 1.59–1.55 (m, 1H), 1.56–1.52 (m, 2H), 1.12–1.02 (m, 1H), 0.87 (dd, J = 12.6, 6.8 Hz, 3H).
Claims
1. A method for preparing a compound of formula I, characterized in that, Comprising the following steps: A. The compound of formula II reacts with the compound of formula VII in the presence of a base and a solvent to obtain the compound of formula III, wherein the base is selected from one of KHMDS, LiHMDS or NaHMDS; B. In the presence of a solvent and a base, the compound of formula III undergoes a Dess-Martin oxidation reaction with the Dess-Martin reagent to obtain the compound of formula IV; C. The compound of formula IV undergoes a Wittig-Horner reaction with the compound of formula VIII in the presence of a base to obtain the compound of formula V, wherein the base is selected from one of sodium hydride, n-butyllithium, potassium tert-butoxide, sodium tert-butoxide, KHMDS or NaHMDS; D. The compound of formula V undergoes a reduction reaction in the presence of a reducing agent and a solvent to obtain the compound of formula VI, wherein the reducing agent is borane / R-(+)-Me-CBS; E. Under acidic conditions, the protecting group on the hydroxyl group of the compound of formula VI is removed to obtain the compound of formula I; wherein R is selected from one of trimethylsilyl ether, triethylsilyl ether, tert-butyldimethylsilyl ether, tert-butyldiphenylsilyl ether, triisopropylsilyl ether.
2. The preparation method of a compound of formula I according to claim 1, characterized in that, The reaction temperature in step B is -5 - 15 °C.
3. The preparation method of a compound of formula I according to claim 1, characterized in that, The basic reagent in step B is selected from one of sodium bicarbonate and pyridine.
4. The preparation method of a compound of formula I according to claim 1, characterized in that, The basic reagent in step C is selected from one of potassium tert-butoxide and sodium tert-butoxide.
5. The preparation method of a compound of formula I according to claim 1, characterized in that, The acidic reagent in step E is selected from one of p-toluenesulfonic acid and dilute hydrochloric acid.
6. Use of a compound with the following structural formula in the preparation of iloprost 。
Citation Information
Patent Citations
Prostacyclin derivatives
US20090325976A1
Prostacyclin derivatives
WO2011003058A1
Improved process for the preparation of iioprost
IN201641044269A