CN113372376A

CN113372376A - Temsirolimus intermediate compound VIII

Info

Publication number: CN113372376A
Application number: CN202010163221.6A
Authority: CN
Inventors: 郑艺; 白文钦
Original assignee: Lunan Pharmaceutical Group Corp
Current assignee: Lunan Pharmaceutical Group Corp
Priority date: 2020-03-10
Filing date: 2020-03-10
Publication date: 2021-09-10

Abstract

The invention belongs to the field of pharmaceutical chemicals, and particularly relates to a temsirolimus intermediate compound VIII. The preparation method of the temsirolimus intermediate compound VIII provided by the invention comprises the following steps: dissolving a compound 2,2,4, 4-tetraisopropyl-7-methyl-1, 3,5,2, 4-trioxasidosiloxane-7-carboxylic acid and a first organic base in an organic solvent, adding a compound 2,4, 6-trichlorobenzoyl chloride, continuously stirring and reacting at a controlled temperature to obtain 2,4, 6-trichlorobenzoyl chloride protected trioxasidosiloxane ester, adding sirolimus, and continuously reacting to obtain a compound VIII. The temsirolimus prepared by the intermediate compound VIII provided by the invention is subjected to protective group removal under the acid-free and water-free conditions, so that the generation of ring-opening impurities is effectively prevented, and the method is suitable for industrial production.

Description

Temsirolimus intermediate compound VIII

Technical Field

The invention belongs to the field of pharmaceutical chemicals, and particularly relates to a temsirolimus intermediate compound VIII.

Background

Temsirolimus (temsirolimus), a derivative of sirolimus, the product of which the chemical name is sirolimus 42- [ 3-hydroxy-2- (hydroxymethyl) -2-methylpropionate ] which is the first application in the mTOR inhibitor drugs for treating cancers, was developed by the american hui pharmaceutical company, and is approved by the FDA through a quick approval channel for the treatment of advanced renal cell carcinoma at 5 months 2007, and the structural formula is as follows:

most of the prior process routes take rapamycin as a main raw material, and a synthetic method of temsirolimus is reported for the first time in U.S. Pat. No. 5,5362718, and the route is as follows:

the synthetic method has the defects that the reaction has no regioselectivity, the 31-hydroxyl and the 42-hydroxyl of the rapamycin are easy to esterify when synthesizing temsirolimus, the separation and purification difficulty of the product is high, and the yield is only 60-70%.

For solving the problem of poor regioselectivity in the synthesis process, the Chinese patent application CN102796115 can selectively protect 31-hydroxyl by utilizing the principle that the steric hindrance of 42-hydroxyl is lower than that of 31-hydroxyl. The method can effectively improve the regioselectivity of the esterification reaction, but has the defects of multiple steps and complicated operation.

Chinese patent application CN102796115 reports that siloxyether with higher regioselectivity is taken as a protective group, and the siloxyether is hydrolyzed under acidic conditions to obtain temsirolimus, wherein the synthetic route is as follows:

although the method improves the selectivity of 42-hydroxyl reaction, the deprotection of the siloxane needs to be carried out under an acidic condition, the rapamycin structure is easy to generate a degradation reaction in an acidic aqueous solution to generate a rapamycin ring-opening compound, and the degradation route is as follows:

rapamycin ring-openers not only reduce the yield of the product but also increase the difficulty of product isolation.

Therefore, the problem to be solved at present is to explore a process route for synthesizing temsirolimus, which has the advantages of high regioselectivity, simple operation, short production period, higher yield and more suitability for industrial production.

Disclosure of Invention

In order to solve the problems of poor regioselectivity, low yield, low purity, difficult product separation and the like in the preparation process of temsirolimus in the prior art, the invention provides a temsirolimus intermediate VIII and a preparation method of the compound; the method has the advantages of short reaction route, simple and convenient operation, milder reaction, economy, environmental protection and high yield, and is suitable for industrial production.

The invention is realized by the following technical scheme:

a temsirolimus intermediate compound represented by formula VIII:

a preparation method of temsirolimus intermediate compound VIII comprises the following steps: dissolving a compound IV and a first organic base in an organic solvent, adding a compound V, namely 2,4, 6-trichlorobenzoyl chloride, continuously stirring and reacting at a controlled temperature, detecting that a compound VI is obtained after the reaction is finished and is not separated, adding a compound VII, namely sirolimus and a second organic base, and continuously reacting to obtain a compound VIII, wherein the reaction route is as follows:

preferably, the first organic base is one or a combination of triethylamine, pyridine, N-methylmorpholine and N, N-diisopropylethylamine, and pyridine is particularly preferred.

Preferably, the organic solvent is selected from one or a combination of N, N-dimethylformamide, dichloromethane, trichloromethane, carbon tetrachloride, tetrahydrofuran, ethyl acetate and toluene, and particularly preferred is trichloromethane.

Preferably, the feeding molar ratio of the compound IV, the first organic base and the compound V is as follows: 1: 1.1-2.0, especially preferably 1:1.2: 1.2.

Preferably, the second organic base is one or two selected from 2, 6-lutidine, 4-methylpyridine, pyridine and triethylamine, and pyridine is particularly preferred.

In a preferred embodiment, the feeding molar ratio of the compound IV, the compound viii and the second organic base is: 1: 1.2-2.2: 1.5-2.2, and particularly preferably 1:1.4: 1.8.

In a preferred scheme, the reaction temperature is-10-30 ℃, and preferably 10 ℃.

In a preferred embodiment, after the reaction is finished, a post-treatment operation is required, specifically: after TLC detection, the organic phase is washed with neutral phosphate buffer, dried and concentrated under reduced pressure, and the product (V) is isolated by silica gel column chromatography_{Petroleum ether}：V_{Ethyl acetate}＝5:1)。

Wherein the preparation method of the compound IV comprises the following steps: adding a compound II, namely 2, 2-bis (hydroxymethyl) propionic acid and alkali into an organic solvent in sequence, adding a compound III, namely 1, 3-dichloro-1, 1,3, 3-tetraisopropyl disiloxane, stirring at a controlled temperature, and reacting to obtain a compound IV, wherein the reaction route is as follows:

in a preferred embodiment, the base may be one or a combination of diethylamine, triethylamine, pyridine, N-diisopropylethylamine and potassium carbonate, wherein triethylamine is particularly preferred.

In a preferable embodiment, the feeding molar ratio of the compound II, the compound III and the base is 1: 1.1-2.0: 2.0-3.0, and particularly preferably 1:1.2: 2.5.

Preferably, the organic solvent is one or a combination of N, N-dimethylformamide, dichloromethane, acetonitrile, chloroform and tetrahydrofuran, and particularly preferably acetonitrile.

In a preferable scheme, the reaction temperature is 0-40 ℃, and particularly preferably 20 ℃.

In a preferred embodiment, after the reaction is finished, a post-treatment operation is required, specifically: after the reaction is finished, cooling the reaction solution, adjusting the pH value of the solution to 5-6, then dropwise adding deionized water (the volume ratio of the solvent to the deionized water is 1:1), stirring for crystallization, filtering and drying to obtain a compound IV; the crystallization temperature is-30 ℃ to 0 ℃.

The use of the compound VIII for preparing temsirolimus.

The compound VIII is used for preparing temsirolimus, and the preparation method comprises the following steps: dissolving the compound VIII in an organic solvent, adding a catalyst, carrying out temperature-controlled stirring reaction, and obtaining temsirolimus after TLC detection reaction, wherein the synthetic route is as follows:

preferably, the catalyst is selected from one or a combination of tetrabutylammonium fluoride, methyltriethylammonium fluoride, tetramethylammonium fluoride and tetraethylammonium fluoride, wherein tetrabutylammonium fluoride is particularly preferred.

In a preferred embodiment, the feeding molar ratio of the compound VIII to the catalyst is 1: 2.0-5.0, and particularly preferably 1: 4.0.

Preferably, the organic solvent is selected from one or a combination of dichloromethane, chloroform, ethyl acetate and tetrahydrofuran, wherein chloroform is particularly preferred.

In a preferred scheme, the reaction temperature is 0-30 ℃, and particularly preferably 20 ℃.

In a preferred embodiment, after the reaction is finished, a post-treatment operation is required, specifically: after TLC detection, the organic phase is washed with neutral phosphate buffer, dried and concentrated under reduced pressure, and the product (V) is isolated by silica gel column chromatography_{Petroleum ether}：V_{Ethyl acetate}＝3:1)。

Compared with the prior art, the invention has the following technical effects:

1. provides a new temsirolimus intermediate compound VIII and a new method for preparing temsirolimus by using the compound, and the whole synthesis method has simple operation, high reaction yield and high purity of the obtained product;

2. the protective group of temsirolimus prepared by the intermediate compound VIII provided by the invention is removed under the acid-free and water-free conditions, so that the generation of ring-opening impurities is effectively prevented.

In conclusion, the invention provides a novel compound and a novel method for synthesizing temsirolimus by using the compound, the method avoids using dangerous chemical reagents, the synthesized intermediate does not generate new impurities, the traditional catalyst is replaced by a green catalyst, the reaction is milder, the economic performance and the environmental protection are realized, the yield is higher, and the method is suitable for industrial production.

Detailed Description

The invention is further illustrated by the following examples. It should be properly understood that: the examples of the present invention are intended to be illustrative only and not to be limiting, and therefore, the present invention is intended to be simply modified within the scope of the present invention as claimed.

The structure of the novel compound obtained by the invention is confirmed:

structure characterization of Compound IV

High resolution mass spectrum of compound IV: ESI-HRMS: M/z 377.2138[ M + H ]]⁺；¹H-NMR(400MHz,CDCl₃):δ11.13(s,1H),3.97(s,4H),1.51-1.67(m,4H),1.11(s,3H),0.85(d,J＝6.6Hz 24H)；¹³C-NMR(100MHz,CDCl₃)δ179,63.8,51.2,22.7,17.3,14.7.

Structural characterization of Compound VIII

High resolution mass spectrum of compound VIII: ESI-HRMS: M/z 1272.75[ M + H ]]⁺；¹H-NMR(400MHz,DMSO-d₆)δ6.47(s,1H),6.40(dd,J＝11.4,13.8Hz,1H),6.23(t,J＝10.2Hz,1H),6.14(m,1H),6.11(m,1H),5.47(dd,J＝10.2,14.4Hz,1H),5.29(d,J＝4.2Hz,1H),5.10(d,J＝10.2Hz,1H),4.98(m,1H),4.94(d,J＝3.6Hz,1H),4.55(t,J＝4.5Hz,2H),4.50(m,1H),4.02(brs,1H),4.02(m,1H),3.96(d,J＝3.6Hz,1H),3.81(s,4H),3.63(d,J＝11.4Hz,1H),3.47(m,4H),3.44-3.12(m,2H),3.30(s,3H),3.26(m,1H),3.16(m,1H),3.15(s,3H),3.05(s,3H),2.73-2.35(m,2H),2.37(m,1H),2.22(m,1H),2.11(m,1H),2.03(m,1H),1.95(m,2H),1.87(m,2H),1.85(m,2H),1.84(m,2H),1.75(s,3H),1.71(m,3H),1.68(s,3H),1.57(m,6H),1.55(m,2H),1.53(m,2H),1.40(m,2H),1.19(m,2H),1.17(m,2H),1.11(s,3H),1.04(s,3H),0.98(d,J＝6.6Hz,3H),0.87(d,J＝6.0Hz,3H),0.85(d,J＝6.6Hz 24H 0.82(d,J＝6.0Hz,3H),0.78(d,J＝6.0Hz,3H),0.73(d,J＝6.6Hz,3H)；¹³C-NMR(100Hz,DMSO-d₆)δ:210.8,208.0,199.3,174.6,169.6,167.4,139.7,138.3,137.6,132.8,130.8,127.4,125.2,99.4,85.9,82.6,80.6,76.2,76.3,74.0,66.6,64.1,64.0,57.7,57.3,55.9,51.2,50.3,45.7,43.9,40.3,40.0,39.9,39.5,38.5,36.3,35.6,35.2,33.8,32.5,30.9,30.1,29.7,26.8,26.6,24.9,23.8,23.8,23.8,23.8,22.0,20.8,17.3,17.0,16.0,15.1,13.9,13.7,10.9。

Preparation of Compound IV

Example 1

Adding 2, 2-bis (hydroxymethyl) propionic acid (13.41g, 0.1mol) and triethylamine (25.30g, 0.25mol) into 90mL of acetonitrile in sequence, adding 1, 3-dichloro-1, 1,3, 3-tetraisopropyl disiloxane (37.85g, 0.12mol), stirring and reacting at the temperature of 20 ℃ for 2 hours, adjusting the pH of a reaction solution to be 5-6 after the reaction is finished, cooling the reaction solution to-20 ℃, dropwise adding 90mL of deionized water, stirring and crystallizing for 2 hours, filtering, and drying in vacuum at the temperature of 40 ℃ to obtain a compound IV, wherein the yield is 98.7%, and the HPLC purity is 99.88%.

Example 2

Adding 2, 2-bis (hydroxymethyl) propionic acid (13.41g, 0.1mol) and diethylamine (18.29g, 0.25mol) into 90mLN, N-dimethylformamide in sequence, adding 1, 3-dichloro-1, 1,3, 3-tetraisopropyl disiloxane (34.70g, 0.11mol), stirring and reacting at 20 ℃ for 2h, adjusting the pH of the reaction solution to 5-6 after the reaction is finished, cooling the reaction solution to-20 ℃, dropwise adding 90mL of deionized water, stirring and crystallizing for 2h, filtering, and drying in vacuum at 40 ℃ to obtain the compound IV with the yield of 94.2% and the HPLC purity of 99.79%.

Example 3

Sequentially adding 90mL of 1.2-dichloroethane into 2, 2-bis (hydroxymethyl) propionic acid (13.41g, 0.1mol) and pyridine (19.78g, 0.25mol), adding 1, 3-dichloro-1, 1,3, 3-tetraisopropyl disiloxane (63.09g, 0.20mol), stirring and reacting at 40 ℃ for 2 hours, adjusting the pH of the reaction solution to 5-6 after the reaction is finished, cooling the reaction solution to-20 ℃, dropwise adding 90mL of deionized water, stirring and crystallizing for 2 hours, filtering, and drying in vacuum at 40 ℃ to obtain the compound IV, wherein the yield is 93.6% and the HPLC purity is 99.75%.

Example 4

Adding 2, 2-bis (hydroxymethyl) propionic acid (13.41g, 0.1mol) and potassium carbonate (34.55g, 0.25mol) into 90mLN, N-dimethylformamide in sequence, adding 1, 3-dichloro-1, 1,3, 3-tetraisopropyl disiloxane (31.54g, 0.10mol), stirring and reacting at 20 ℃ for 2h, after the reaction is finished, adjusting the pH of the reaction solution to 5-6, cooling the reaction solution to-20 ℃, dropwise adding 90mL of deionized water, stirring and crystallizing for 2h, filtering, and drying in vacuum at 40 ℃ to obtain the compound IV, wherein the yield is 91.7%, and the HPLC purity is 99.75%.

Example 5

Sequentially adding 90mL of trichloromethane into 2, 2-bis (hydroxymethyl) propionic acid (13.41g, 0.1mol) and N, N-diisopropylethylamine (32.31g, 0.25mol), adding 1, 3-dichloro-1, 1,3, 3-tetraisopropyl disiloxane (78.86g, 0.25mol), stirring and reacting at the temperature of 0 ℃ for 2 hours, after the reaction is finished, adjusting the pH of the reaction liquid to be 5-6, cooling the reaction liquid to-20 ℃, dropwise adding 90mL of deionized water, stirring and crystallizing for 2 hours, filtering, and drying in vacuum at the temperature of 40 ℃ to obtain a compound IV, wherein the yield is 86.6%, and the HPLC purity is 99.65%.

Example 6

Adding 2, 2-bis (hydroxymethyl) propionic acid (13.41g, 0.1mol) and triethylamine (20.24g, 0.2mol) into 90mL of acetonitrile in sequence, adding 1, 3-dichloro-1, 1,3, 3-tetraisopropyl disiloxane (37.85g, 0.12mol), stirring and reacting at the temperature of 30 ℃ for 2 hours, adjusting the pH of a reaction solution to be 5-6 after the reaction is finished, cooling the reaction solution to-30 ℃, dropwise adding 90mL of deionized water, stirring and crystallizing for 2 hours, filtering, and drying in vacuum at the temperature of 40 ℃ to obtain a compound IV, wherein the yield is 94.6%, and the HPLC purity is 99.82%.

Example 7

Adding 2, 2-bis (hydroxymethyl) propionic acid (13.41g, 0.1mol) and triethylamine (30.36g, 0.3mol) into 90mL of acetonitrile in sequence, adding 1, 3-dichloro-1, 1,3, 3-tetraisopropyl disiloxane (37.85g, 0.12mol), stirring and reacting at the temperature of 20 ℃ for 2 hours, adjusting the pH of a reaction solution to be 5-6 after the reaction is finished, cooling the reaction solution to-35 ℃, dropwise adding 90mL of deionized water, stirring and crystallizing for 2 hours, filtering, and drying in vacuum at the temperature of 40 ℃ to obtain a compound IV, wherein the yield is 95.2%, and the HPLC purity is 99.77%.

Example 8

Adding 2, 2-bis (hydroxymethyl) propionic acid (13.41g, 0.1mol) and triethylamine (18.21g, 0.18mol) into 90mL of acetonitrile in sequence, adding 1, 3-dichloro-1, 1,3, 3-tetraisopropyl disiloxane (37.85g, 0.12mol), stirring and reacting at 45 ℃ for 2h, adjusting the pH of the reaction solution to 5-6 after the reaction is finished, cooling the reaction solution to 5 ℃, dropwise adding 90mL of deionized water, stirring and crystallizing for 2h, filtering, and drying in vacuum at 40 ℃ to obtain a compound IV, wherein the yield is 87.2%, and the HPLC purity is 99.71%.

Example 9

Sequentially adding 2, 2-bis (hydroxymethyl) propionic acid (13.41g, 0.1mol) and triethylamine (32.38g, 0.32mol) into 90mL of acetonitrile, adding 1, 3-dichloro-1, 1,3, 3-tetraisopropyl disiloxane (37.85g, 0.12mol), stirring at 5 ℃ for 2h, adjusting the pH of the reaction solution to 5-6 after the reaction is finished, cooling the reaction solution to-35 ℃, dropwise adding 90mL of deionized water, stirring for crystallization for 2h, filtering, and drying in vacuum at 40 ℃ to obtain a compound IV with the yield of 85.5% and the HPLC purity of 99.67%.

Preparation of Compound VIII

Example 10

Adding compound IV (37.62g, 0.10mmol) and pyridine (9.49g, 0.12mol) into 200mL chloroform in turn, adding 2,4, 6-trichlorobenzoyl chloride (29.27g, 0.12mmol), stirring at 10 deg.C for reaction, after the detection reaction is finished, adding compound V II (127.90g, 0.14mol) and pyridine (14.24g, 0.18mol) into the reaction, continuing the stirring reaction, after the TLC detection reaction is finished, washing the organic phase with 0.2mol/L phosphate buffer solution (800mL), drying the organic phase, concentrating under reduced pressure, and separating the product by silica gel column chromatography (eluent V)_{Petroleum ether}：V_{Ethyl acetate}5:1), yield 98.5%, HPLC purity 99.89%.

Example 11

Adding a compound IV (37.62g, 0.10mmol) and pyridine (8.70g, 0.11mol) into 200mLN, N-dimethylformamide in sequence, adding 2,4, 6-trichlorobenzoyl chloride (29.27g, 0.12mmol) into the mixture, stirring the mixture for reaction at 30 ℃, and after the detection reaction is finished, adding a compound V II (127.90g, 0.14mol) and pyridine (8.70g, 0.11mol) into the mixture,2, 6-lutidine (19.29g, 0.18mol) was added to the reaction and the reaction was continued with stirring, after completion of the TLC detection, the organic phase was washed with 0.2mol/L phosphate buffer (800mL), dried and concentrated under reduced pressure, and the product was isolated by column chromatography on silica gel (eluent V)_{Petroleum ether}：V_{Ethyl acetate}5:1), yield 95.6%, HPLC purity 99.82%.

Example 12

Adding compound IV (37.62g, 0.10mmol) and pyridine (15.82g, 0.20mol) into 200mL of trichloromethane in turn, adding 2,4, 6-trichlorobenzoyl chloride (29.27g, 0.12mmol) to the chloroform, stirring for reaction at 10 ℃, after the detection reaction is finished, adding compound V II (127.90g, 0.14mol) and 4-methylpyridine (16.76g, 0.18mol) into the reaction, continuing to stir for reaction, after the TLC detection reaction is finished, washing the organic phase with 0.2mol/L phosphate buffer solution (800mL), drying the organic phase, concentrating under reduced pressure, and separating the product by silica gel column chromatography (eluent V)_{Petroleum ether}：V_{Ethyl acetate}5:1), yield 93.4%, HPLC purity 99.75%.

Example 13

Adding compound IV (37.62g, 0.10mmol) and pyridine (7.91g, 0.10mol) into 200mL of toluene in turn, stirring at 35 deg.C for reaction, after the detection reaction is finished, adding compound V II (127.90g, 0.14mol) and triethylamine (18.21g, 0.18mol) into the reaction, continuing to stir the reaction, after the TLC detection reaction is finished, washing the organic phase with 0.2mol/L phosphate buffer solution (800mL), drying the organic phase, concentrating under reduced pressure, and separating the product by silica gel column chromatography (eluent V)_{Petroleum ether}：V_{Ethyl acetate}5:1), yield 94.4%, HPLC purity 99.78%.

Example 14

Adding compound IV (37.62g, 0.10mmol) and pyridine (17.40g, 0.22mol) into 200mL tetrahydrofuran in turn, adding 2,4, 6-trichlorobenzoyl chloride (29.27g, 0.12mmol) into the tetrahydrofuran, stirring at 20 ℃, after the detection reaction is finished, adding compound V II (127.90g, 0.14mol) and triethylamine (18.21g, 0.18mol) into the reaction, continuing the stirring reaction, after the TLC detection reaction is finished, washing the organic phase with 0.2mol/L phosphate buffer solution (800mL), drying the organic phase, concentrating under reduced pressure, and performing silica gel columnChromatography of the product (eluent V)_{Petroleum ether}：V_{Ethyl acetate}5:1), yield 86.6%, HPLC purity 99.69%.

Example 15

Adding compound IV (37.62g, 0.10mmol) and N-methylmorpholine (12.14g, 0.12mol) into 200mL of trichloromethane in turn, adding 2,4, 6-trichlorobenzoyl chloride (26.83g, 0.11mmol), stirring at 10 ℃ for reaction, after the detection reaction is finished, adding compound V II (127.90g, 0.14mol) and pyridine (14.24g, 0.18mol) into the reaction, continuing to stir for reaction, after the TLC detection reaction is finished, washing the organic phase with 0.2mol/L phosphate buffer solution (800mL), drying the organic phase, concentrating under reduced pressure, and separating the product by silica gel column chromatography (eluent V)_{Petroleum ether}：V_{Ethyl acetate}5:1), yield 95.5%, HPLC purity 99.83%.

Example 16

Adding compound IV (37.62g, 0.10mmol) and triethylamine (12.14g, 0.12mol) into 200mL of trichloromethane in turn, adding 2,4, 6-trichlorobenzoyl chloride (48.78g, 0.20mmol), stirring at 10 ℃ for reaction, after the detection reaction is finished, adding compound V II (127.90g, 0.14mol) and pyridine (14.24g, 0.18mol) into the reaction, continuing the stirring reaction, after the TLC detection reaction is finished, washing the organic phase with 0.2mol/L phosphate buffer solution (800mL), drying the organic phase, concentrating under reduced pressure, and separating the product by silica gel column chromatography (eluent V)_{Petroleum ether}：V_{Ethyl acetate}5:1), yield 92.8%, HPLC purity 99.78%.

Example 17

Adding compound IV (37.62g, 0.10mmol) and N, N-diisopropylethylamine (15.51g, 0.12mol) into 200mL chloroform in turn, adding 2,4, 6-trichlorobenzoyl chloride (53.66g, 0.22mmol), stirring at 10 deg.C for reaction, after the detection reaction is finished, adding compound V II (127.90g, 0.14mol), pyridine (14.24g, 0.18mol) into the reaction, continuing to stir for reaction, after the TLC detection reaction is finished, washing the organic phase with 0.2mol/L phosphate buffer solution (800mL), drying the organic phase, concentrating under reduced pressure, and separating the product by silica gel column chromatography (eluent V)_{Petroleum ether}：V_{Ethyl acetate}5:1), yield 87.6%, HPLC purity 99.71%.

Example 18

Adding compound IV (37.62g, 0.10mmol) and N-methylmorpholine (12.14g, 0.12mol) into 200mL of trichloromethane in turn, adding 2,4, 6-trichlorobenzoyl chloride (29.27g, 0.12mmol) into the chloroform, stirring for reaction at 10 ℃, after the detection reaction is finished, adding compound V II (109.63g, 0.12mol) and pyridine (14.24g, 0.18mol) into the reaction, continuing to stir for reaction, after the TLC detection reaction is finished, washing the organic phase with 0.2mol/L phosphate buffer solution (800mL), drying the organic phase, concentrating under reduced pressure, and separating the product by silica gel column chromatography (eluent V)_{Petroleum ether}：V_{Ethyl acetate}5:1), yield 94.3%, HPLC purity 99.82%.

Example 19

Adding compound IV (37.62g, 0.10mmol) and triethylamine (12.14g, 0.12mol) into 200mL of trichloromethane in turn, adding 2,4, 6-trichlorobenzoyl chloride (29.27g, 0.12mmol) into the trichloromethane, stirring the mixture at 10 ℃ for reaction, after the detection reaction is finished, adding compound V II (200.98g, 0.22mol) and pyridine (14.24g, 0.18mol) into the reaction, continuing the stirring reaction, after the TLC detection reaction is finished, washing the organic phase with 0.2mol/L phosphate buffer solution (800mL), drying the organic phase, concentrating the organic phase under reduced pressure, and separating the product by silica gel column chromatography (eluent V)_{Petroleum ether}：V_{Ethyl acetate}5:1), yield 92.3%, HPLC purity 99.73%.

Example 20

Adding compound IV (37.62g, 0.10mmol) and pyridine (9.49g, 0.12mol) into 200mL chloroform in turn, adding 2,4, 6-trichlorobenzoyl chloride (29.27g, 0.12mmol) to the chloroform, stirring at 15 deg.C for reaction, after the detection reaction is finished, adding compound V II (91.36g, 0.10mol) and pyridine (14.24g, 0.18mol) into the reaction, continuing the stirring reaction, after the TLC detection reaction is finished, washing the organic phase with 0.2mol/L phosphate buffer solution (800mL), drying the organic phase, concentrating under reduced pressure, and separating the product by silica gel column chromatography (eluent V)_{Petroleum ether}：V_{Ethyl acetate}5:1), yield 87.3%, HPLC purity 99.71%.

Example 21

Compound IV (37.62g, 0.10mmol) and pyridine (9.49g, 0.12mol) were added successively to 200mL trichloromethane is added with 2,4, 6-trichlorobenzoyl chloride (29.27g, 0.12mmol) and stirred for reaction at 5 ℃, after the detection reaction is finished, a compound V II (228.39g, 0.25mol) and pyridine (14.24g, 0.18mol) are added into the reaction, the reaction is continued to be stirred, after the TLC detection reaction is finished, an organic phase is washed by 0.2mol/L phosphate buffer solution (800mL), the organic phase is decompressed and concentrated after being dried, and a product is separated by silica gel column chromatography (eluent V)_{Petroleum ether}：V_{Ethyl acetate}5:1), yield 85.6%, HPLC purity 99.66%.

Example 22

Adding compound IV (37.62g, 0.10mmol) and pyridine (9.49g, 0.12mol) into 200mL of trichloromethane in turn, adding 2,4, 6-trichlorobenzoyl chloride (29.27g, 0.12mmol) into the chloroform, stirring at 10 deg.C for reaction, after the detection reaction is finished, adding compound V II (127.90g, 0.14mol) and pyridine (11.87g, 0.15mol) into the reaction, continuing the stirring reaction, after the TLC detection reaction is finished, washing the organic phase with 0.2mol/L phosphate buffer solution (800mL), drying the organic phase, concentrating under reduced pressure, and separating the product by silica gel column chromatography (eluent V)_{Petroleum ether}：V_{Ethyl acetate}5:1), yield 94.4%, HPLC purity 99.81%.

Example 23

Adding compound IV (37.62g, 0.10mmol) and pyridine (9.49g, 0.12mol) into 200mL of trichloromethane in turn, adding 2,4, 6-trichlorobenzoyl chloride (29.27g, 0.12mmol) into the chloroform, stirring at 10 deg.C for reaction, after the detection reaction is finished, adding compound V II (127.90g, 0.14mol) and pyridine (17.40g, 0.22mol) into the reaction, continuing the stirring reaction, after the TLC detection reaction is finished, washing the organic phase with 0.2mol/L phosphate buffer solution (800mL), drying the organic phase, concentrating under reduced pressure, and separating the product by silica gel column chromatography (eluent V)_{Petroleum ether}：V_{Ethyl acetate}5:1), yield 93.5%, HPLC purity 99.76%.

Example 24

After the completion of the reaction, compound IV (37.62g, 0.10mmol) and pyridine (9.49g, 0.12mol) were added to 200mL of chloroform in this order, 2,4, 6-trichlorobenzoyl chloride (29.27g, 0.12mmol) was added thereto and the mixture was stirred at 10 ℃ to react, and after completion of the reaction, compound V II (127.90g, 0.14mol), pyridine (10.28g,0.13mol) is added into the reaction, the reaction is continuously stirred, after the TLC detection reaction is finished, the organic phase is washed by 0.2mol/L phosphate buffer solution (800mL), the organic phase is dried and then is decompressed and concentrated, and the product is separated by silica gel column chromatography (eluent V)_{Petroleum ether}：V_{Ethyl acetate}5:1), yield 86.5%, HPLC purity 99.77%.

Example 25

Adding compound IV (37.62g, 0.10mmol) and pyridine (9.49g, 0.12mol) into 200mL of trichloromethane in turn, adding 2,4, 6-trichlorobenzoyl chloride (29.27g, 0.12mmol) into the chloroform, stirring at 10 deg.C for reaction, after the detection reaction is finished, adding compound V II (127.90g, 0.14mol) and pyridine (19.78g, 0.25mol) into the reaction, continuing the stirring reaction, after the TLC detection reaction is finished, washing the organic phase with 0.2mol/L phosphate buffer solution (800mL), drying the organic phase, concentrating under reduced pressure, and separating the product by silica gel column chromatography (eluent V)_{Petroleum ether}：V_{Ethyl acetate}5:1), yield 85.2%, HPLC purity 99.68%.

Preparation of temsirolimus

Example 26

Dissolving compound VIII (12.72g, 10.0mmol) in 130mL chloroform, adding tetrabutylammonium fluoride (10.46g, 40.0mmol), stirring at 20 deg.C for reaction, after TLC detection reaction, washing organic phase with 0.2mol/L phosphate buffer solution (1000mL), drying organic phase, concentrating under reduced pressure, and performing silica gel column chromatography (eluent V)_{Petroleum ether}：V_{Ethyl acetate}And (3: 1) separating the product to obtain the temsirolimus with the yield of 99.8 percent and the HPLC purity of 99.88 percent.

Example 27

Dissolving compound VIII (12.72g, 10.0mmol) in 130mL chloroform, adding methyltriethylammonium fluoride (5.41g, 40.0mmol), stirring at 0 deg.C for reaction, after TLC detection reaction, washing the organic phase with 0.2mol/L phosphate buffer (1000mL), drying the organic phase, concentrating under reduced pressure, and performing silica gel column chromatography (eluent V)_{Petroleum ether}：V_{Ethyl acetate}The product is separated by 3:1), and the yield is 97.8 percent, and the HPLC purity is 99.85 percent.

Example 28

The compoundVIII (12.72g, 10.0mmol) is dissolved in 130mL of chloroform, tetramethylammonium fluoride (3.73g, 40.0mmol) is added, the reaction is stirred at 30 ℃, after the TLC detection reaction is finished, the organic phase is washed by 0.2mol/L phosphate buffer solution (1000mL), the organic phase is dried and concentrated under reduced pressure, and the mixture is chromatographed by silica gel column (eluent V)_{Petroleum ether}：V_{Ethyl acetate}The product is separated according to the ratio of 3:1), and the yield is 97.0 percent, and the HPLC purity is 99.82 percent.

Example 29

Dissolving compound VIII (12.72g, 10.0mmol) in 130mL of chloroform, adding tetraethylammonium fluoride (6.69g, 40.0mmol), stirring at-5 deg.C for reaction, after TLC detection, washing the organic phase with 0.2mol/L phosphate buffer (1000mL), drying the organic phase, concentrating under reduced pressure, and performing silica gel column chromatography (eluent V)_{Petroleum ether}：V_{Ethyl acetate}And (3: 1) separating the product to obtain the temsirolimus, wherein the yield is 98.2 percent, and the HPLC purity is 99.85 percent.

Example 30

Dissolving compound VIII (12.72g, 10.0mmol) in 130mL dichloromethane, adding tetrabutylammonium fluoride (5.23g, 20.0mmol), stirring at 20 deg.C for reaction, after TLC detection of reaction completion, washing organic phase with 0.2mol/L phosphate buffer solution (1000mL), drying organic phase, concentrating under reduced pressure, and performing silica gel column chromatography (eluent V)_{Petroleum ether}：V_{Ethyl acetate}The product is separated by 3:1), and the yield is 95.4 percent, and the HPLC purity is 99.81 percent.

Example 31

Dissolving compound VIII (12.72g, 10.0mmol) in 130mL acetonitrile, adding tetrabutylammonium fluoride (13.07g, 50.0mmol), stirring at 20 deg.C for reaction, after TLC detection, washing the organic phase with 0.2mol/L phosphate buffer solution (1000mL), drying the organic phase, concentrating under reduced pressure, and performing silica gel column chromatography (eluent V)_{Petroleum ether}：V_{Ethyl acetate}And (3: 1) separating the product to obtain the temsirolimus, wherein the yield is 94.6 percent, and the HPLC purity is 99.75 percent.

Example 32

Compound VIII (12.72g, 10.0mmol) was dissolved in 130mL of tetrahydrofuran, tetrabutylammonium fluoride (3.92g, 15.0mmol) was added, and the reaction was stirred at 20 ℃ to obtain a solution, TAfter the LC detection reaction, the organic phase was washed with 0.2mol/L phosphate buffer (1000mL), dried, concentrated under reduced pressure, and chromatographed on silica gel column (eluent V)_{Petroleum ether}：V_{Ethyl acetate}The product was isolated as 3:1) to yield temsirolimus in 86.6% yield and 99.77% HPLC purity.

Example 33

Dissolving compound VIII (12.72g, 10.0mmol) in 130mL chloroform, adding tetrabutylammonium fluoride (14.38g, 55.0mmol), stirring at 20 deg.C for reaction, after TLC detection reaction, washing organic phase with 0.2mol/L phosphate buffer solution (1000mL), drying organic phase, concentrating under reduced pressure, and performing silica gel column chromatography (eluent V)_{Petroleum ether}：V_{Ethyl acetate}The product was isolated as 3:1) to yield temsirolimus in 85.6% yield with an HPLC purity of 99.72%.

Comparative examples

2, 2-bis (hydroxymethyl) propionic acid (5.00g, 37.28mmol) and triethylamine (26.41g, 0.26mol) are added into 50.00ml of N, N-dimethylformamide, the mixture is stirred in an ice-water bath, tert-butyldimethylsilyl chloride (19.60g, 0.13mol) is added, the mixture is heated to room temperature and reacts for 5-8 h to obtain 10.0g of compound 1-1, the yield is 36.2%, and the HPLC purity is 92.23%.

Compound 1-1(5.00g, 13.79mmol) and triethylamine (2.10g, 20.75mmol) were added to 50.00ml of dichloromethane, and 2,4, 6-trichlorobenzoyl chloride (3.30g, 13.53mmol) was added with stirring, and after reacting at room temperature for 6 hours, 10.00ml of dichloromethane containing rapamycin (4.20g, 4.60mmol) and 4- (N, N-dimethylamino) pyridine (2.25g, 18.38mmol) was slowly dropped thereto while controlling the reaction temperature at 0 ℃ to 5 ℃ and reacting for 12 hours to obtain Compound B-1 in 45.3% yield and 96.56% HPLC purity.

Adding the compound B-1(1.00g, 0.79mmol) into a solvent containing 15.00ml of acetone, stirring, adding 1N hydrochloric acid (2.38ml) and reacting in an ice-water bath for 1-2 h to obtain the temsirolimus, wherein the yield is 79.5%, and the HPLC purity is 95.87%.

Claims

1. A temsirolimus intermediate compound represented by formula VIII:

2. the intermediate compound VIII according to claim 1, which is prepared by a process comprising the steps of: dissolving a compound IV and a first organic base in an organic solvent, adding a compound V, namely 2,4, 6-trichlorobenzoyl chloride, continuously stirring and reacting at a controlled temperature, detecting that a compound VI is obtained after the reaction is finished and is not separated, adding a compound VII, namely sirolimus and a second organic base, and continuously reacting to obtain a compound VIII, wherein the reaction route is as follows:

3. the preparation method according to claim 2, wherein the first organic base is one or a combination of triethylamine, pyridine, N-methylmorpholine and N, N-diisopropylethylamine.

4. The method according to claim 2, wherein the second organic base is selected from one or two of 2, 6-lutidine, 4-methylpyridine, pyridine and triethylamine.

5. The preparation method according to claim 2, wherein the compound IV, the first organic base, the compound V, the compound viii, and the second organic base are fed in a molar ratio of: 1: 1.1-2.0: 1.2-2.2: 1.5-2.2.

6. The preparation method according to claim 2, wherein the organic solvent is selected from one or a combination of N, N-dimethylformamide, dichloromethane, chloroform, carbon tetrachloride, tetrahydrofuran, ethyl acetate and toluene; the reaction temperature is-10-30 ℃.

7. The process according to claim 2, wherein the process for the preparation of compound IV comprises the steps of: adding a compound II, namely 2, 2-bis (hydroxymethyl) propionic acid and alkali into an organic solvent in sequence, adding a compound III, namely 1, 3-dichloro-1, 1,3, 3-tetraisopropyl disiloxane, stirring at a controlled temperature, and reacting to obtain a compound IV, wherein the reaction route is as follows:

8. the method according to claim 7, wherein the base is one or a combination of diethylamine, triethylamine, pyridine, N-diisopropylethylamine and potassium carbonate.

9. The method according to claim 7, wherein the compound II, the compound III and the base are fed in a molar ratio of 1:1.1 to 2.0:2.0 to 3.0.

10. Use of compound v III according to claim 1 for the preparation of temsirolimus, comprising the steps of: deprotection of a compound VIII under the action of a catalyst to obtain temsirolimus I, wherein the synthetic route is as follows: