阅读说明：本技术 一种艾日布林中间体er806060的合成方法 (Synthetic method of eribulin intermediate ER806060 ) 是由 刘�文 王甜甜 张栋 袁文龙 姜雪峰 俞斐 于 2019-08-22 设计创作，主要内容包括：本发明公开了一种如式(b)所示的艾日布林中间体ER806060(CAS:871348-08-2)的合成方法,以(S)-3-((2R,3R,5S))-5-烯丙基-3-(苄氧基)-4-((苯基磺酰基)亚甲基)四氢呋喃-2-基)丙烷-1,2-二基二苯甲酸酯((S)-3-((2R,3R,5S)-5-allyl-3-(benzyloxy)-4-((phenylsulfonyl)methylene)tetr ahydrofuran-2-yl)propane-1,2-diyl dibenzoate)作为原料,经一步脱保护基苄基反应合成所述艾日布林中间体ER806060。本发明合成方法具有产率高,操作简便,成本低,产生不可控的杂质少,适合工业化生产等优点。本发明所述艾日布林中间体ER806060结构为：(The invention discloses a synthesis method of eribulin intermediate ER806060(CAS:871348-08-2) shown in formula (b), which is characterized in that (S) -3- ((2R,3R,5S)) -5-allyl-3- (benzyloxy) -4- ((phenylsulfonyl) methylene) tetrahydrofuran-2-yl) propane-1,2-diyl dibenzoate ((S) -3- ((2R,3R,5S) -5-allyl-3- (phenyloxy) -4- ((phenylsulfonyl) methyl) tetrahydrofuran-1, 2-diyl dibenzoate) is used as a raw material, and the eribulin intermediate ER806060 is synthesized through deprotection and benzyl reaction. The synthetic method has the advantages of high yield, simple and convenient operation, low cost, less uncontrollable generated impurities, suitability for industrial production and the like. The eribulin intermediate ER806060 disclosed by the invention has the structure as follows:)

1. A synthetic method of eribulin intermediate ER806060 is characterized in that a compound shown as a formula a and a Lewis acid reagent are subjected to debenzylation protecting group reaction in an organic solvent to obtain eribulin intermediate ER806060 shown as a formula b, the synthetic process is shown as a scheme (A),

wherein R is H or C1-C6 alkyl.

2. The synthetic method of claim 1 wherein the lewis acid reagent is one or more of titanium tetrachloride, tin tetrachloride, aluminum trichloride, ferric trichloride, boron tribromide.

3. The synthesis method according to claim 1, wherein the organic solvent is an aprotic solvent selected from one or more of dichloromethane, 1, 2-dichloroethane, tetrahydrofuran, carbon tetrachloride, chlorobenzene, toluene and xylene.

4. The method of synthesis of claim 1, wherein the compound of formula a, the lewis acid reagent, are present in a molar ratio of 1: (1-10).

5. The synthetic method of claim 1 wherein the temperature of the debenzylation protection reaction is 0-140 ℃.

6. The synthesis method according to claim 1, wherein the debenzylation protection reaction time is 1-10 h.

7. The eribulin intermediate ER806060 is characterized in that the structure is shown as formula (b):

wherein R is H or C1-C6 alkyl.

Technical Field

The invention belongs to the technical field of chemical synthesis, and particularly relates to a synthetic method of eribulin intermediate ER806060(CAS: 871348-08-2).

Background

Eribulin as an anticancer agent, the compound can be assembled by three fragments through a series of chemical reactions, and one of the key fragments is ER806067 (CAS: 871348-24-2). One lead compound synthesized from this fragment is ER 806060.

The prior patent or literature (WO2005/118565A1) discloses that in the process of synthesizing ER 806060: the method has the defects of complex operation, low yield, more three wastes, poor reaction stability, uncontrollable impurity generation and the like, so that the production risk is high, the cost is high, and the method is not suitable for industrial production.

Among them, the method described in patent document (WO2005/118565a1) is a method of synthesizing compound B by removing a protecting group benzyl group from compound a as a raw material through TMSI, and the synthesis process is shown in scheme (B):

wherein R is H or CH₃Or CH₃CH₂。

The method for removing the protecting group benzyl by adopting TMSI has obvious and inevitable defects: 1. TMSI used in the reaction tends to produce uncontrollable various impurities that are difficult to remove; 2. the reaction is carried out at high temperature, the temperature needs to be immediately changed after the reaction is finished, the conditions are harsh, and industrialization is difficult to realize; 3. the reaction system is quenched by ammonia water, the quenching and stirring time is long (needs to stay overnight), the industrialized production time is obviously prolonged, and the workshop cost is greatly increased.

Disclosure of Invention

In order to overcome the defects in the prior art, the invention provides a novel industrial synthesis method of Eribulin intermediate ER806060 for the first time. The synthesis method takes the compound shown in the formula a as a raw material, and synthesizes eribulin intermediate ER806060 through Lewis acid debenzylation protection reaction. The method has the advantages of high reaction stability, simple operation, economy, environmental protection, high yield (about 80 percent), little uncontrollable acrobatics, suitability for industrial production and the like.

The invention provides a synthetic method of eribulin intermediate ER806060 shown in formula (b), the synthetic process is shown in a route (A),

wherein R is H or alkyl of C1-C6;

preferably, R is H or CH₃Or CH₃CH₂。

The invention relates to a synthesis method of eribulin intermediate ER806060, which comprises the following specific steps:

in an organic solvent, the compound of the formula a and a Lewis acid reagent are subjected to debenzylation protecting group reaction to obtain a compound of a formula b.

In this step, the organic solvent is an aprotic solvent commonly used in the art, and is selected from one or more of dichloromethane, 1, 2-dichloroethane, Tetrahydrofuran (THF), carbon tetrachloride, chlorobenzene, toluene, xylene, and the like; preferably, dichloromethane.

In the step, the Lewis acid reagent is one or more of titanium tetrachloride, ferric trichloride, stannic chloride, aluminum trichloride boron tribromide and the like; preferably, it is titanium tetrachloride.

In this step, the molar ratio of the compound of formula a to the lewis acid reagent is 1: (1-10); preferably, 1: (1-5); further preferably, is 1: 5.

in the step, the temperature of the debenzylation protecting group reaction is 0-140 ℃; preferably, it is 30 ℃.

In the step, the time for the debenzylation protecting group reaction is 1-10 h; preferably, 3 to 8 hours; further preferably, it is 5 h.

In this step, the reaction stability is high, the operation is simple, the reaction yield is high (about 80%), and the risk is small.

The method also comprises a purification step before obtaining the compound of the formula b, wherein the purification step is carried out on a crude product of the compound of the formula b obtained after the debenzylation protecting group reaction to obtain the compound of the formula b.

Wherein, the specific step of the purification is that the crude compound of formula b is subjected to flash column chromatography (silica gel (5 wt of the input amount), and the eluent is petroleum ether/ethyl acetate-4/1), and the component containing the product compound of formula b is collected and concentrated to obtain the compound of formula b.

Meanwhile, the invention also discloses a possible reaction mechanism of the reaction, which is shown as the following formula (C):

the compound of the formula a and titanium tetrachloride firstly generate a1, a chlorine anion leaves, the chlorine anion attacks benzyl carbenium ion to generate an intermediate a2, benzyl chloride is removed to obtain an intermediate a3, and the compound of the formula b is obtained by quenching.

The invention also provides an eribulin intermediate ER806060 prepared by the method.

The invention provides an eribulin intermediate ER806060, which has a structure shown in a formula (b):

wherein R is H or alkyl of C1-C6;

preferably, R is H or CH₃Or CH₃CH₂。

The invention is different from the prior art or the most main innovation points are as follows:

compared with the existing synthesis method, the synthesis method of the invention which adopts Lewis acid reagent such as titanium tetrachloride as the reagent for removing the benzyl protecting group has the obvious advantages that: (1) the invention adopts Lewis acid reagent such as titanium tetrachloride as a debenzylation protecting group for reaction, and can avoid the problems of complicated operation, high risk, high cost caused by the generation of uncontrollable impurities and the like caused by the use of TMSI; (2) lewis acid reagents such as titanium tetrachloride are adopted as debenzylation protecting groups for reaction, so that the longer quenching time required by the post-treatment of TMSI can be avoided, and the production cost is further reduced. The invention reduces the generation of uncontrollable impurities in the reaction, shortens the reaction and treatment time, reduces the operation difficulty and obviously reduces the cost.

In one embodiment, the industrial synthetic route of eribulin intermediate ER806060 of formula (b) is as follows:

wherein R is H or alkyl of C1-C6;

preferably, R is H or CH₃Or CH₃CH₂。

The method has the advantages of short reaction time, short treatment time, simple and convenient operation, recyclable waste liquid, high yield (about 80%), few uncontrollable impurities and low production cost, and is very suitable for industrial mass production.

Corresponding full-name corresponding table used for short names in the specification

Entry	Abbreviations	Full scale
			1	DCM	Methylene dichloride
2	TMSI	Trimethyliodisilane
			3	TiCl4	Titanium tetrachloride

Detailed Description

The present invention will be described in further detail with reference to the following specific examples. The procedures, conditions, experimental methods and the like for carrying out the present invention are general knowledge and common general knowledge in the art except for the contents specifically mentioned below, and the present invention is not particularly limited.

Example 1

Synthesis of compound b (as exemplified by R ═ H):

scheme 1:

dichloromethane (60L, 10V) was added to a 100L reactor under nitrogen protection, followed by addition of (S) -3- ((2R,3R,5S)) -5-allyl-3- (benzyloxy) -4- ((phenylsulfonyl) methylene) tetrahydrofuran-2-yl) propane-1,2-diyl dibenzoate ((S) -3- ((2R,3R,5S) -5-allyl-3- (phenyloxy) -4- ((phenylsulfonyl) methyl) tetr anhydrofuran-2-yl) propane-1,2-diyl dibenzoate) (6kg, 9.19mol), dropwise addition of titanium tetrachloride (8.72kg, 45.95mol) at 30 ℃ for 5 hours, detection by HPLC or TLC, and completion of the reaction. Cooling to 10 ℃, adding water (30L, 5V), standing for liquid separation, extracting the water phase twice with dichloromethane (6L, 1V), combining the organic phases, washing with saturated aqueous sodium bicarbonate solution (6L, 1V), concentrating the organic phase to 1.5V (9L) under reduced pressure, performing flash column chromatography, and eluting with petroleum ether/ethyl acetate to obtain the compound of formula b (4.14kg, 7.35 mol).

¹H NMR(400MHz,CHLOROFORM-d)δppm 2.15-2.35(m,5H)3.09-3.21(m,2H)3.40(dt,J＝8.50,5.65Hz,1H)3.98(q,J＝6.44Hz,1H)4.37-4.44(m,1H)4.54-4.64(m,2H)4.77-4.94(m,2H)5.54-5.79(m,2H)7.43(q,J＝7.50Hz,4H)7.51-7.66(m,4H)7.67-7.75(m,1H)7.93(d,J＝7.34Hz,2H)8.04(dd,J＝13.45,7.34Hz,4H)。

The method synthesizes the compound shown in the formula b through the reaction of removing benzyl protecting groups from titanium tetrachloride, the yield is high (80%), the operation flow is simple, the reaction safety is high, uncontrollable impurities are not generated, waste solvents (petroleum ether and ethyl acetate) generated in the post-treatment process of the step can be recycled, the generated three wastes are less, and compared with the method described in the existing patent literature, the method has obvious advantages and is suitable for industrial production.

Meanwhile, the invention also carries out relevant optimization on the step, and the specific implementation scheme is as follows:

scheme 1-1:

under the protection of nitrogen, 1, 2-dichloroethane (200mL, 10V) or toluene (200mL, 10V) or chlorobenzene (200mL, 10V) or carbon tetrachloride (200mL, 10V) or dichloromethane (200mL, 10V) or xylene (200mL, 10V) or tetrahydrofuran (200mL, 10V) is added into a 500mL reaction flask, then (S) -3- ((2R,3R,5S)) -5-allyl-3- (benzyloxy) -4- ((phenylsulfonyl) methylene) tetrahydrofuran-2-yl) propane-1,2-diyl dibenzoate ((S) -3- ((2R,3R,5S) -5-allyl-3- (phenyloxy) -4- ((phenylsulfonyl) methyl) tetrol anhydrofuran-2-yl) propane-1 is added, 2-diyl dibenzoate) (20g, 0.03mol), titanium tetrachloride (28.45g, 0.15mol) was added dropwise at 20 ℃ and reacted at 30 ℃ for 5 hours, followed by HPLC or TLC detection to terminate the reaction. Cooling to 10 deg.C, adding water (100mL, 5V), standing for liquid separation, extracting the water phase twice with dichloromethane (20mL, 1V), combining the organic phases, washing with saturated sodium bicarbonate water solution (20mL, 1V), concentrating the organic phase to 1.5V (30mL) under reduced pressure, performing flash column chromatography, and eluting with petroleum ether/ethyl acetate to obtain the compound of formula b.

Compound of formula b obtained from dichloromethane system (13.79g, 0.0245 mol); toluene system derived compound of formula b (8.62g, 0.015 mol); compound of formula b obtained from chlorobenzene system (6.90g, 0.012 mol); xylene system to give the compound of formula b (0.56g, 0.001 mol); 1, 2-Dichloromethane system (4.50g, 0.008 mol); the compound of formula b obtained in the carbon tetrachloride system (2.81g, 0.005 mol); the tetrahydrofuran system does not produce the compound of formula b.

The reaction solvent identified in this scheme is therefore preferably dichloromethane.

Schemes 1-2:

under nitrogen protection, a 500mL reaction flask was charged with dichloromethane (200mL, 10V), followed by addition of (S) -3- ((2R,3R,5S)) -5-allyl-3- (benzyloxy) -4- ((phenylsulfonyl) methylene) tetrahydrofuran-2-yl) propane-1,2-diyl dibenzoate ((S) -3- ((2R,3R,5S) -5-allyl-3- (benzyloxy) -4- ((phenylsulfonyl) methyl) tetr anhydrofuran-2-yl) propane-1,2-diyl dibenzoate) (20g, 0.03mol), dropwise addition of titanium tetrachloride (28.45g, 0.15mol) or addition of tin tetrachloride (39.01g, 0.15mol) or iron trichloride (24.33g, 0.15mol) or aluminum trichloride (20.00 g), 0.15mol) or boron tribromide (37.58g, 0.15mol), and the reaction is finished after 5 hours at 30 ℃ and HPLC or TLC detection. Cooling to 10 deg.C, adding water (100mL, 5V), standing for liquid separation, extracting the water phase twice with dichloromethane (20mL, 1V), combining the organic phases, washing with saturated sodium bicarbonate water solution (20mL, 1V), concentrating the organic phase to 1.5V (30mL) under reduced pressure, performing flash column chromatography, and eluting with petroleum ether/ethyl acetate to obtain the compound of formula b.

Titanium tetrachloride (28.45g, 0.15mol) system to give a compound of formula b (13.79g, 0.0245 mol); compound of formula b (11.02g, 0.0196mol) obtained from a system of tin tetrachloride (39.01g, 0.15 mol); a compound of formula b (9.65g, 0.0172mol) obtained from a system of ferric trichloride (24.33g, 0.15 mol); aluminium trichloride (20.00g, 0.15mol) system; boron tribromide (37.58g, 0.15mol) system to give a compound of formula b (9.00g, 0.016 mol).

The lewis acid identified in this scheme is therefore preferably titanium tetrachloride.

Schemes 1-3:

under the protection of nitrogen, a 500mL reaction flask was charged with dichloromethane (200mL, 10V), and then (S) -3- ((2R,3R,5S)) -5-allyl-3- (benzyloxy) -4- ((phenylsulfonyl) methylene) tetrahydrofuran-2-yl) propane-1,2-diyl dibenzoate ((S) -3- ((2R,3R,5S) -5-allyl-3- (benzyloxy) -4- ((phenylsulfonyl) methyl) tetr anhydrofuran-2-yl) propane-1,2-diyl dibenzoate) (20g, 0.03mol), titanium tetrachloride (39.83g, 0.21mol) or titanium tetrachloride (28.45g, 0.15mol) or titanium tetrachloride (17.44g, 0.09mol) was added dropwise at 20 ℃ and reacted for 5 hours at 30 ℃, HPLC or TLC detection, the reaction is finished. Cooling to 10 deg.C, adding water (100mL, 5V), standing for liquid separation, extracting the water phase twice with dichloromethane (20mL, 1V), combining the organic phases, washing with saturated sodium bicarbonate water solution (20mL, 1V), concentrating the organic phase to 1.5V (30mL) under reduced pressure, performing flash column chromatography, and eluting with petroleum ether/ethyl acetate to obtain the compound of formula b.

Titanium tetrachloride (17.44g, 0.09mol) system to give a compound of formula b (10.34g, 0.018 mol); titanium tetrachloride (28.45g, 0.15mol) system to give a compound of formula b (13.79g, 0.0245 mol); titanium tetrachloride (39.83g, 0.21mol) system to give a compound of formula b (13.79g, 0.0245 mol).

Thus in this scheme the lewis acid titanium tetrachloride/compound a molar ratio is tentatively 5: 1.

schemes 1-4:

under the protection of nitrogen, dichloromethane (200mL, 10V) was added to a 500mL reaction flask, and then (S) -3- ((2R,3R,5S)) -5-allyl-3- (benzyloxy) -4- ((phenylsulfonyl) methylene) tetrahydrofuran-2-yl) propane-1,2-diyl dibenzoate ((S) -3- ((2R,3R,5S) -5-allyl-3- (benzyloxy) -4- ((phenylsulfonyl) methyl) tetr anhydrofuran-2-yl) propane-1,2-diyl dibenzoate) (20g, 0.03mol), titanium tetrachloride (28.45g, 0.15mol) was added dropwise at 20 ℃, and the reaction was completed after 3 hours at 30 ℃ or 5 hours or 7 hours by HPLC or TLC detection. Cooling to 10 deg.C, adding water (100mL, 5V), standing for liquid separation, extracting the water phase twice with dichloromethane (20mL, 1V), combining the organic phases, washing with saturated sodium bicarbonate water solution (20mL, 1V), concentrating the organic phase to 1.5V (30mL) under reduced pressure, performing flash column chromatography, and eluting with petroleum ether/ethyl acetate to obtain the compound of formula b.

The reaction was carried out for 3 hours with the remainder of the starting materials, and the compound of formula b (8.62g, 0.015mol) was obtained as a system; the compound of formula b obtained after 5 hours of reaction (13.79g, 0.0245 mol); the reaction time was 7 hours to give a compound of formula b (13.79g, 0.0245 mol).

The optimum reaction time is therefore temporarily set to 5 hours in this case.

Schemes 1-5:

under the protection of nitrogen, dichloromethane (200mL, 10V) is added into a 500mL reaction bottle, then (S) -3- ((2R,3R,5S)) -5-allyl-3- (benzyloxy) -4- ((phenylsulfonyl) methylene) tetrahydrofuran-2-yl) propane-1,2-diyl dibenzoate ((S) -3- ((2R,3R,5S) -5-allyl-3- (benzyloxy) -4- ((phenylsulfonyl) methyl) tetr anhydrofuran-2-yl) propane-1,2-diyl dibenzoate) (20g, 0.03mol), titanium tetrachloride (28.45g, 0.15mol) is added dropwise at 20 ℃, the reaction is carried out for 5 hours at 20 ℃ or for 5 hours at 30 ℃ or for 5 hours at 40 ℃, and HPLC or TLC detection is carried out, the reaction was complete. Cooling to 10 deg.C, adding water (100mL, 5V), standing for liquid separation, extracting the water phase twice with dichloromethane (20mL, 1V), combining the organic phases, washing with saturated sodium bicarbonate water solution (20mL, 1V), concentrating the organic phase to 1.5V (30mL) under reduced pressure, performing flash column chromatography, and eluting with petroleum ether/ethyl acetate to obtain the compound of formula b.

The reaction was carried out at 20 ℃ for 5 hours with the remainder of the starting materials, and the compound of formula b (5.63g, 0.01mol) was obtained from the system; the compound of formula b obtained (13.79g, 0.0245mol) was reacted at 30 ℃ for 5 hours; the reaction was carried out at 40 ℃ for 5 hours to obtain a compound of formula b (13.79g, 0.0245 mol).

The optimum reaction temperature is therefore temporarily set to 30 ℃ in this case.

Scheme 2(WO2005/118565A 1):

the process proposed in this patent document is to synthesize compound B starting from compound a using TMSI as a debenzylating protecting group, as shown in scheme (B):

the specific embodiment is as follows:

synthesis of Compound b:

under the protection of nitrogen, compound a (S) -3- ((2R,3R,5S)) -5-allyl-3- (benzyloxy) -4- ((phenylsulfonyl) methylene) tetrahydrofuran-2-yl) propane-1,2-diyl dibenzoate ((S) -3- ((2R,3R,5S) -5-allyl-3- (benzyloxy) -4- ((phenylsulfonyl) methyl) tet hydrofuran-2-yl) propane-1,2-diyl dibenzoate (20g, 0.03mol) was dissolved in toluene (50ml, 2.5v), acetonitrile (50ml, 2.5v), TMSI (24g, 0.12mol) was added dropwise at 30 ℃, the system was heated to 60 ℃ and reacted for 2 hours at 60 ℃, TLC or HPLC was completed, the temperature was reduced to-15 ℃, then 25% ammonia (100ml, 5v) was added dropwise, stirred overnight at 30 ℃, separated, the aqueous phase was extracted with toluene (100ml, 5v), the organic phases were combined, washed successively with 10% aqueous sodium sulfite (100ml, 5v), 1N hydrochloric acid (100ml, 5v), 5% sodium bicarbonate (100ml, 5v), saturated brine (100ml, 5v), dried over anhydrous sodium sulfate (4g, 0.2wt), concentrated to dryness at 55 ℃ to give a crude product, and column chromatography was performed to give compound b (12.07g,0.021mol) with a yield of 70%.

¹H NMR(400MHz,CHLOROFORM-d)δppm 2.15-2.35(m,5H)3.09-3.21(m,2H)3.40(dt,J＝8.50,5.65Hz,1H)3.98(q,J＝6.44Hz,1H)4.37-4.44(m,1H)4.54-4.64(m,2H)4.77-4.94(m,2H)5.54-5.79(m,2H)7.43(q,J＝7.50Hz,4H)7.51-7.66(m,4H)7.67-7.75(m,1H)7.93(d,J＝7.34Hz,2H)8.04(dd,J＝13.45,7.34Hz,4H)。

The disadvantage of this step is that when TMSI debenzylation protecting group is used, the reaction must be carried out at high temperature, once the reaction is finished, the temperature must be immediately reduced, or the temperature must be reduced in advance to quench when the raw material is not reacted, and uncontrollable impurity iodized compound is easy to generate, and the amount of waste water generated by this step of operation is relatively large, thereby further increasing the production cost and increasing the complexity of operation.

The protection of the present invention is not limited to the above embodiments. Variations and advantages that may occur to those skilled in the art may be incorporated into the invention without departing from the spirit and scope of the inventive concept, and the scope of the appended claims is intended to be protected.