阅读说明：本技术 一种伊洛前列素的制备方法 (Preparation method of iloprost ) 是由 陈寅波 张晓煜 李亮 杨玉雷 于 2020-05-16 设计创作，主要内容包括：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 medicine synthesis, and relates to a preparation method of iloprost, which specifically comprises the steps of taking a compound shown in a formula II as a raw material, obtaining a compound shown in a formula III through Wittig reaction and valeric acid side chain splicing, obtaining a single E type through liquid phase separation, generating aldehyde through dessimutane oxidation, namely a compound shown in a formula IV, obtaining a compound shown in a formula V through Wittig-Hornor reaction and alkynyl side chain compound shown in a formula VIII, obtaining a compound shown in a formula VI through chiral reduction, and finally removing a hydroxyl protecting group to obtain iloprost. Compared with other routes, the method has the advantages of few reaction steps, simple and easily-controlled process, high total yield, easy industrial production and the like.)

1. A process for the preparation of a compound of formula i, comprising the steps of:

A. reacting a compound shown in a formula II with a compound shown in a formula VII in the presence of alkali and a solvent to obtain a compound shown in a formula III,

B. in the presence of a solvent and alkali, performing Dess-Martin oxidation reaction on the compound shown in the formula III and a Dess-Martin reagent to obtain a compound shown in the 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 a compound of formula V,

D. the compound of the formula V is subjected to reduction reaction in the presence of a reducing agent and a solvent to obtain a compound of a formula VI,

E. removing protecting group on hydroxyl from compound of formula VI under acidic condition to obtain compound of formula I

Wherein R is one of trimethylsilyl ether, triethylsilyl ether, tert-butyldimethylsilyl ether, tert-butyldiphenylsilyl ether and triisopropylsilyl ether.

2. The process of claim 1, wherein the base in step a is selected from KHMDS, LiHMDS, NaHMDS.

3. The process for the preparation of a compound of formula i according to claim 1, wherein the reaction temperature in step B is-5 to 15 ℃.

4. The process of claim 1, wherein the alkaline reagent in step B is selected from sodium bicarbonate and pyridine.

5. The process of claim 1, wherein the basic agent in step C is selected from the group consisting of sodium hydrogen, n-butyllithium, potassium tert-butoxide, sodium tert-butoxide, KHMDS, and NaHMDS.

6. The process of claim 1, wherein the basic reagent in step C is selected from potassium tert-butoxide and sodium tert-butoxide.

7. The process of claim 1, wherein the reducing agent in step D is selected from borane/R- (+) -Me-CBS, sodium borohydride/diethyl methoxyborane.

8. The process of claim 1, wherein the acidic reagent in step E is selected from p-toluenesulfonic acid and dilute hydrochloric acid.

9. A compound of the formula

10. Use of a compound according to claim 9 for the preparation of iloprost.

Technical Field

The invention belongs to the field of drug synthesis, and relates to a preparation method of iloprost.

Background

Iloprost (Iloprost), developed by the research and development of bayer corporation, is sold under the trade name Ventavis (myritavir), is approved by the FDA in the united states for treating pulmonary hypertension (PAH) in 12-29 th of 2004, is approved by the national food and drug administration for domestic marketing in 2006, and is one of four imported targeted drugs currently approved for treating pulmonary 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]Octan-3-ylidene } -pentanoic acid having the molecular formula C₂₂H₃₂O₄The structural formula is as follows:

there are many reports on the synthesis of iloprost, and basically all the synthetic routes are more than 20 steps, for example, in Chemistry-A European Journal,2006,12(21): 5610-.

For example, Guido J.Kramp et al J.AM.CHEM.SOC.2005,127,17910-17920, first prepare a chiral bicyclic mother nucleus by a chiral induction method, access a chiral alkynyl side chain in one step, and finally access a valeric acid side chain in two steps to prepare iloprost. This route provides a method for the formation of the E-type double bond when building the pentanoic acid side chain, but the reaction conditions are severe, requiring six days at-62 ℃.

The two types of 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 segmented connection of two side chains can increase the proportion of the required E-type double bond, but the conditions are harsh, the length of the synthetic route is further increased, and the yield is further reduced.

In the patents WO2011003058 and US2009325976, the two side chains are introduced through one-step reaction after the chiral mother ring is prepared, but the E-type/Z-type mixture of about 2:1 is obtained by introducing the valeric acid side chain, which causes great waste on the chiral mother ring prepared through a plurality of steps of reactions.

Therefore, the process research on the synthesis of iloprost, the optimization of the synthesis route and the process operation, the reduction of steps, the improvement of yield and the improvement of purity have very important significance on the industrial production of iloprost.

Disclosure of Invention

The invention provides a preparation method of iloprost, which comprises the following steps:

A. reacting a compound shown in a formula II with a compound shown in a formula VII in the presence of alkali and a solvent to obtain a compound shown in a formula III,

B. in the presence of a solvent and alkali, performing Dess-Martin oxidation reaction on the compound shown in the formula III and a Dess-Martin reagent to obtain a compound shown in the 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 a compound of formula V,

D. the compound of the formula V is subjected to reduction reaction in the presence of a reducing agent and a solvent to obtain a compound of a formula VI,

E. removing protecting group on hydroxyl from compound of formula VI under acidic condition to obtain compound of formula I

Wherein R is one of trimethylsilyl ether, triethylsilyl ether, tert-butyldimethylsilyl ether, tert-butyldiphenylsilyl ether and triisopropylsilyl ether.

In some embodiments, the base in step a is one of KHMDS, LiHMDS, NaHMDS; in some embodiments, the base in step a is KHMDS. In some embodiments, the reaction temperature in step A is 5 to 40 ℃.

In some embodiments, the reaction temperature in step B is-5 to 15 ℃; in some embodiments, the reaction temperature in step B is from 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; in some embodiments, the reaction solvent in step B is dichloromethane.

In some embodiments, the basic agent in step C is selected from one of sodium hydrogen, n-butyl lithium, potassium tert-butoxide, sodium tert-butoxide, KHMDS, NaHMDS; in some embodiments, the basic agent in step C is potassium tert-butoxide or sodium tert-butoxide.

In some embodiments, the reducing agent in step D is selected from one of borane/R- (+) -Me-CBS, sodium borohydride/diethyl methoxyborane. In some embodiments, the reducing agent in step D is borane/R- (+) -Me-CBS. In some embodiments, the reaction temperature in step D is from-5 to 30 ℃.

In some embodiments, the acidic reagent in step E is selected from one of p-toluenesulfonic acid, dilute hydrochloric acid. In some embodiments, the acidic agent in step E is p-toluenesulfonic acid. In some embodiments, the reaction temperature in step E is 10 to 50 ℃.

In another aspect, the present invention provides compounds of the structural formula:

in another aspect, the use of a compound of formula III-1, formula IV-1, formula V-1 for the preparation of iloprost.

The invention provides a new synthesis route of iloprost, and has the advantages of few reaction steps, simple and easily-controlled process, high total yield, mild reaction conditions, easy industrial production and the like.

Detailed Description

The present application is further illustrated with reference to specific examples. It should be understood that these examples are for illustrative purposes only and do not limit the scope of the present application.

EXAMPLE 1 Synthesis of Compound of formula III-1

The compound of formula VII (31.2g, 70.4mmol) was added to 170ml of anhydrous tetrahydrofuran under nitrogen, and 1M KHMDS/THF solution (105.6ml, 105.6mmol) was added dropwise at room temperature and stirred for 30 min. The compound of formula II-1 (5.0g, 17.6mmol) dissolved in dry tetrahydrofuran was added dropwise and stirred for 24 h. Adding water (50ml) into the reaction solution to quench the reaction, and dropwise adding 0.5N diluted hydrochloric acid to adjust the pH value to 6-7. The layers were separated, the aqueous layer was extracted with ethyl acetate (50 ml. times.3), and the organic layers were combined and washed with water (50 ml. times.3) and saturated brine (50ml) in that order. Dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the filtrate was evaporated to dryness and purified by column chromatography to give a pale yellow oil (3.9 g). Resolution by preparative liquid phase gave the title compound III-1, diastereomer of form E, 32.6g, 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 Compound of formula IV-1

Under the protection of nitrogen, the compound of formula III-1 (2.0g, 5.4mmol) is dissolved in 200ml of anhydrous dichloromethane, cooled to 0 ℃, added with dessimutan oxidant (11.5g, 27mmol) and sodium bicarbonate (6.8g, 86.4mmol), stirred for 30min, heated to 10 ℃ and reacted for 12 h. Adding water (10ml) into the system to quench the reaction, adjusting the pH to 6-7 by using saturated sodium bicarbonate aqueous solution, separating the solution, extracting a water layer by using dichloromethane (20ml multiplied by 3), and combining organic phases. Dried over anhydrous sodium sulfate, filtered over celite, and the filtrate evaporated to dryness to give a crude colourless oil (2g) which was directly charged to the next reaction.

EXAMPLE 3 Synthesis of Compound of formula V-1

Potassium tert-butoxide (3.7g, 32.8mmol) was added to 75ml of anhydrous tetrahydrofuran under nitrogen, the compound of formula VIII (6.34g, 27.3mmol) dissolved in 63ml of anhydrous tetrahydrofuran was added dropwise at room temperature, and the mixture was stirred for 30min at 45 ℃. The reaction was cooled to room temperature and the compound of formula IV-1 (2g, 5.5mol) dissolved in 36ml of anhydrous tetrahydrofuran was added dropwise and stirred at room temperature for 2 h. Water (50ml) is added into the system to quench the reaction, and the pH is adjusted to 6-7 by 0.5N diluted hydrochloric acid. The layers were separated, the aqueous layer was extracted with ethyl acetate (20 ml. times.3), and the organic layers were combined and washed successively with saturated aqueous sodium thiosulfate (20 ml. times.3), water (20 ml. times.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 give a pale yellow oil (1.4g) in 54% yield in two steps.

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 Compound of formula VI-1

Under the protection of nitrogen, 2.0M borane dimethylsulfide/THF solution (2.8ml, 5.50mmol) is dissolved in 66ml of anhydrous dichloromethane, the reaction system is cooled to-5 ℃, 1.0M R- (+) -Me-CBS/toluene solution (5.50ml, 5.50mmol) is added, and stirring is carried out for 15 min. The compound of formula V-1 (1.3g, 2.75mmol) dissolved in 28ml of anhydrous dichloromethane was added dropwise, the temperature was raised to 10 ℃ and stirred for 15 min. The reaction mixture was quenched with 10ml of water, separated, the aqueous layer was extracted with DCM (10ml × 3), the organic phases were combined, the organic phase was washed successively with water (10ml × 3) and saturated brine (10ml), dried over anhydrous sodium sulfate, filtered, 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 iloprost, a Compound of formula I

A compound of the formula VI-1 (1.03g, 2.2mmol) is dissolved in 65ml of acetone and 15ml of water, p-toluenesulfonic acid monohydrate (0.42g, 2.2mmol) is added and stirring is carried out at 30 ℃ for 12 h. Saturated aqueous sodium bicarbonate (20ml) was added, and the acetone was evaporated by concentration under reduced pressure. The residual 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 (10ml), 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 a yield of 92%.

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)。