CN113683544B - A kind of preparation method of iloprost - Google Patents
A kind of preparation method of iloprost Download PDFInfo
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- CN113683544B CN113683544B CN202010415896.5A CN202010415896A CN113683544B CN 113683544 B CN113683544 B CN 113683544B CN 202010415896 A CN202010415896 A CN 202010415896A CN 113683544 B CN113683544 B CN 113683544B
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- C07C405/005—Analogues or derivatives having the five membered ring replaced by other rings
- C07C405/0075—Analogues or derivatives having the five membered ring replaced by other rings having the side-chains or their analogues or derivatives attached to a condensed ring system
- C07C405/0083—Analogues or derivatives having the five membered ring replaced by other rings having the side-chains or their analogues or derivatives attached to a condensed ring system which is only ortho or peri condensed, e.g. carbacyclins
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Abstract
本发明属于药物合成领域，涉及一种伊洛前列素的制备方法，具体而言，以式Ⅱ化合物为原料，经过Wittig反应和戊酸侧链拼接得到式Ⅲ化合物，E型/Z型约2:1，通过液相分离得到单一的E型，通过戴斯马丁氧化生成醛即式Ⅳ化合物，再通过Wittig‑Hornor反应和炔基侧链式Ⅷ化合物拼接得到式Ⅴ化合物，手性还原得到式Ⅵ化合物，最后脱去羟基保护基得到伊洛前列素。相对于其它路线反应步骤少、工艺简便易控、总收率高、易于工业化生产等优点。 The invention belongs to the field of drug synthesis, and relates to a method for preparing iloprost. Specifically, a compound of formula II is used as a raw material, and a compound of formula III is obtained through Wittig reaction and valeric acid side chain splicing, with an E type/Z type of about 2:1, and a single E type is obtained through liquid phase separation, and an aldehyde, i.e., a compound of formula IV, is generated through Dess-Martin oxidation, and then a compound of formula V is obtained through Wittig-Hornor reaction and splicing of an alkynyl side chain compound of formula VIII, and a compound of formula VI is obtained through chiral reduction, and finally the hydroxyl protecting group is removed to obtain iloprost. Compared with other routes, the method has the advantages of fewer reaction steps, simple and easy-to-control process, high total yield, and easy industrial production.
Description
Technical Field
The invention belongs to the field of medicine synthesis, and relates to a preparation method of iloprost.
Background
Iloprost (Iloprost), developed by bayer company under the trade name Ventavis (vantavid), was approved by the FDA in the united states at 12/29 th 2004 for the treatment of pulmonary hypertension (PAH), was approved by the national food and drug administration in 2006 for domestic marketing, and is one of four imported targeted drugs currently available for the treatment of pulmonary hypertension. Iloprost is chemically named 5- { (E) - (1 s,5s,6r,7 r) -7-hydroxy-6- [ (E) - (3 s,4 rs) -3-hydroxy-4-methyl-1-oct-6-ynyl ] -bicyclo [3.3.0] oct-3-subunit } -pentanoic acid, molecular formula C 22H32O4, structural formula:
There are many reports of Guan Yiluo synthetic literature of prostaglandins, which are all 20 steps or more, for example Gais H J, etc. in Chemistry-A European Journal,2006,12 (21): 5610-5617, chiral dicyclic parent nucleus is prepared by resolution of the racemate, then chiral alkynyl side chains are connected in two sections, and finally valeric acid side chains are connected to prepare iloprost.
For example, guido J.Kramp et al in J.AM.CHEM.SOC.2005,127,17910-17920, a chiral double-ring master is prepared by a chiral induction method, a chiral alkynyl side chain is connected in one step, and finally a valeric side chain is connected in two sections to prepare iloprost. This route provides a method for forming E-type double bonds when constructing the valeric acid side chains, but the reaction conditions are severe, and the reaction is carried out for six days at-62 ℃.
The two synthetic methods are mostly linear synthetic routes, and have the defects of long steps, low total yield, complex operation, harsh reaction conditions, expensive reagents and the like, and the sectional connection of two side chains can increase the proportion of required E-type double bonds, but the conditions are harsh, the length of the synthetic route is increased, and the yield is further reduced.
In patent WO2011003058 and US2009325976, the two side chains are respectively introduced through one-step reaction after the chiral parent ring is prepared, but the E type/Z type mixture of about 2:1 is obtained after the valeric acid side chain is introduced, which causes great waste on the chiral parent ring prepared through a plurality of steps of reaction.
Therefore, the synthesis of the iloprost is subjected to process research, the synthesis route and the process operation are optimized, the steps are reduced, the yield is improved, and the purity is improved, so that the method has very important significance for industrial production of the iloprost.
Disclosure of Invention
The invention provides a preparation method of iloprost, which comprises the following steps:
A. reacting the compound of formula II with the compound of formula VII in the presence of a base and a solvent to obtain a compound of formula III,
B. in the presence of solvent and alkali, the compound of formula III and Dess-Martin reagent undergo Dess-Martin oxidation reaction to obtain compound of formula IV,
C. The compound of formula IV and the compound of formula VIII are subjected to Wittig-Horner reaction in the presence of alkali to obtain the compound of formula V,
D. the compound of the formula V undergoes a reduction reaction in the presence of a reducing agent and a solvent to obtain a compound of the formula VI,
E. Removing the protecting group on the hydroxyl group of the compound of the formula VI under acidic conditions to obtain the compound of the formula I
Wherein R is one of trimethyl silyl ether, triethyl silyl ether, tertiary butyl dimethyl silyl ether, tertiary butyl diphenyl silyl ether and triisopropyl silyl ether.
In some embodiments, the base in step A is one of KHMDS, liHMDS, naHMDS, and in some embodiments, the base in step A is KHMDS. In some embodiments, the reaction temperature in step a is 5-40 ℃.
In some embodiments, the reaction temperature in step B is-5 to 15 ℃, and in some embodiments, the reaction temperature in step B is 0 to 10 ℃. In some embodiments, the alkaline agent in step B is selected from one of sodium bicarbonate, pyridine. In some embodiments, the reaction solvent in step B is one of chloroform, 1, 2-dichloroethane, acetonitrile, dichloromethane, and in some embodiments, the reaction solvent in step B is dichloromethane.
In some embodiments, the alkaline agent in step C is selected from one of sodium hydrogen, n-butyllithium, potassium t-butoxide, sodium t-butoxide, KHMDS, naHMDS, and in some embodiments, the alkaline agent in step C is potassium t-butoxide or sodium t-butoxide.
In some embodiments, the reducing agent in step D is selected from one of borane/R- (+) -Me-CBS, 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 ℃.
In some embodiments, the acidic reagent in step E is selected from one of p-toluene sulfonic acid, dilute hydrochloric acid. In some embodiments, the acidic reagent in step E is p-toluene sulfonic acid. In some embodiments, the reaction temperature in step E is 10-50 ℃.
In another aspect, the invention provides a compound of the formula:
In another aspect, the use of a compound of formula III-1, formula IV-1, formula V-1 in the preparation of iloprost.
The invention provides a new synthetic route of iloprost, which has the advantages of few reaction steps, simple and easy control of the process, high total yield, mild reaction conditions, easy industrial production and the like.
Detailed Description
The application will be further illustrated with reference to specific examples. It is understood that these examples are only for illustrating the present application and are not intended to limit the scope of the present application.
EXAMPLE 1 Synthesis of Compounds of formula III-1
The compound of formula VII (31.2 g,70.4 mmol) was added to 170ml of anhydrous tetrahydrofuran under nitrogen, 1M KHMDS/THF solution (105.6 ml,105.6 mmol) was added dropwise at room temperature and stirred for 30min. A compound of formula II-1 (5.0 g,17.6 mmol) dissolved in anhydrous tetrahydrofuran was added dropwise and stirred for 24h. Water (50 ml) is added into the reaction liquid to quench the reaction, and 0.5N dilute hydrochloric acid is added dropwise to adjust the pH to 6-7. The mixture was separated, the aqueous phase was extracted with ethyl acetate (50 ml. Times.3), and the organic phases were combined and washed with water (50 ml. Times.3) and then with saturated brine (50 ml). Dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the filtrate was evaporated to dryness and purified by column to give a pale yellow oil (3.9 g). Resolution by preparative liquid phase gives the title compound III-1, diastereomer form E, 32.6g in 45% yield.
MS:391.5[M+Na]+.1H NMR(400MHz,DMSO)δ11.96(s,1H),5.17(t,J＝7.2Hz,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＝3.0Hz,6H).
EXAMPLE 2 Synthesis of Compounds of formula IV-1
Under the protection of nitrogen, the compound (2.0 g,5.4 mmol) of the formula III-1 is dissolved in 200ml of anhydrous dichloromethane, cooled to 0 ℃, and a dessert-Martin oxidant (11.5 g,27 mmol) and sodium bicarbonate (6.8 g,86.4 mmol) are added, stirred for 30min, heated to 10 ℃ and reacted for 12h. The reaction was quenched by adding water (10 ml), adjusting pH to 6-7 with saturated aqueous sodium bicarbonate, separating the solution, extracting the aqueous layer with dichloromethane (20 ml. Times.3), and combining the organic phases. Dried over anhydrous sodium sulfate, filtered through celite, and the filtrate was evaporated to dryness to give a crude colorless oil (2 g) which was directly put into the next reaction.
EXAMPLE 3 Synthesis of Compound of formula V-1
Potassium tert-butoxide (3.7 g,32.8 mmol) was added to 75ml of anhydrous tetrahydrofuran under nitrogen, and the compound of formula VIII (6.34 g,27.3 mmol) dissolved in 63ml of anhydrous tetrahydrofuran was added dropwise at room temperature, and the mixture was stirred for 30min at 45 ℃. The reaction system was cooled to room temperature, and a compound of formula IV-1 (2 g,5.5 mol) dissolved in 36ml of anhydrous tetrahydrofuran was added dropwise thereto, followed by stirring at room temperature for 2 hours. Water (50 ml) is added into the system to quench the reaction, and 0.5N dilute hydrochloric acid is used for adjusting the pH to 6-7. The mixture was separated, the aqueous phase was extracted with ethyl acetate (20 ml. Times.3), and the organic phases were combined and washed successively with a saturated aqueous sodium thiosulfate solution (20 ml. Times.3), water (20 ml. Times.3) and saturated brine (20 ml). Drying over anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure, and purifying by column to obtain pale yellow oily substance (1.4 g), the yield of the two steps is 54%.
MS:495.1[M+Na]+.1H NMR(400MHz,DMSO)δ12.02(s,1H),6.85–6.71(m,1H),6.19(dd,J＝15.7,6.0Hz,1H),5.23(t,J＝7.0Hz,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＝9.1Hz,6H).
EXAMPLE 4 Synthesis of Compounds of formula VI-1
2.0M borane dimethyl sulfide/THF solution (2.8 ml,5.50 mmol) was dissolved in 66ml anhydrous dichloromethane under nitrogen protection, the reaction system was cooled to-5℃and 1.0M R- (+) -Me-CBS/toluene solution (5.50 ml,5.50 mmol) was added and stirred for 15min. A compound of formula V-1 (1.3 g,2.75 mmol) dissolved in 28ml of anhydrous dichloromethane was added dropwise, warmed to 10℃and stirred for 15min. To the reaction solution was added 10ml of water, which was quenched, separated, the aqueous layer was extracted with DCM (10 ml. Times.3), the organic phases were combined, washed with water (10 ml. Times.3) and saturated brine (10 ml) in this order, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness and purified by column chromatography to give a colorless oil (1.03 g). The yield thereof was found to be 67%.
MS:497.2[M+Na]+.1H NMR(600MHz,DMSO)δ5.51–5.45(m,1H),5.40–5.35(m,1H),5.21(t,J＝7.0Hz,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＝6.4Hz,3H),0.83(s,9H),0.01–-0.02(m,6H).
EXAMPLE 5 Synthesis of the Compound iloprost of formula I
The compound of formula VI-1 (1.03 g,2.2 mmol) was dissolved in 65ml of acetone and 15ml of water, p-toluenesulfonic acid monohydrate (0.42 g,2.2 mmol) was added and stirred at 30℃for 12h. Saturated aqueous sodium hydrogencarbonate (20 ml) was added thereto, and the mixture was concentrated under reduced pressure to evaporate the acetone. The remaining aqueous phase was extracted with ethyl acetate (10 ml. Times.3), and the organic phases were combined, washed successively with water (10 ml. Times.3) and saturated brine (10 ml), dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness and purified by column to give 0.40g of a pale yellow oil as iloprost in 92% yield.
MS:383.1[M+Na]+.1H NMR(600MHz,DMSO)δ11.97(s,1H),5.54–5.41(m,1H),5.39–5.28(m,1H),5.20(t,J＝7.0Hz,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 (6)
1. A process for the preparation of a compound of formula I comprising the steps of:
A. Reacting the compound of formula II 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 solvent and alkali, the compound of formula III and Dess-Martin reagent undergo Dess-Martin oxidation reaction to obtain compound of formula IV,
C. the compound of formula IV and the compound of formula VIII are subjected to Wittig-Horner reaction in the presence of alkali to obtain the compound of formula V, wherein the alkali is selected from one of sodium hydrogen, n-butyllithium, potassium tert-butoxide, sodium tert-butoxide, KHMDS or NaHMDS,
D. the compound of the formula V undergoes a reduction reaction in the presence of a reducing agent and a solvent to obtain a compound of the formula VI, wherein the reducing agent is borane/R- (+) -Me-CBS,
E. removing the protecting group on the hydroxyl group of the compound in the formula VI under the acidic condition to obtain the compound in the formula I,
Wherein R is one of trimethyl silyl ether, triethyl silyl ether, tertiary butyl dimethyl silyl ether, tertiary butyl diphenyl silyl ether and triisopropyl silyl ether.
2. A process for the preparation of a compound of formula I according to claim 1, wherein the reaction temperature in step B is-5-15 ℃.
3. The method for preparing a compound of formula I according to claim 1, wherein the alkaline agent in step B is selected from one of sodium bicarbonate and pyridine.
4. The method of claim 1, wherein the alkaline agent in step C is selected from one of potassium tert-butoxide and sodium tert-butoxide.
5. The process for the preparation of a compound of formula I according to claim 1, wherein the acidic reagent in step E is selected from one of p-toluene sulfonic acid, dilute hydrochloric acid.
6. The use of a compound of the formula in the preparation of iloprost,
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