CN114057792B - Temsirolimus intermediate compounds - Google Patents

Temsirolimus intermediate compounds Download PDF

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CN114057792B
CN114057792B CN202010743121.0A CN202010743121A CN114057792B CN 114057792 B CN114057792 B CN 114057792B CN 202010743121 A CN202010743121 A CN 202010743121A CN 114057792 B CN114057792 B CN 114057792B
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CN114057792A (en
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王申
白文钦
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Lunan Pharmaceutical Group Corp
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6564—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms
    • C07F9/6571—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and oxygen atoms as the only ring hetero atoms
    • C07F9/657163—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and oxygen atoms as the only ring hetero atoms the ring phosphorus atom being bound to at least one carbon atom
    • C07F9/657181—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and oxygen atoms as the only ring hetero atoms the ring phosphorus atom being bound to at least one carbon atom the ring phosphorus atom and, at least, one ring oxygen atom being part of a (thio)phosphonic acid derivative
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D498/18—Bridged systems

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)

Abstract

The invention belongs to the field of pharmaceutical chemicals, and particularly relates to a temsirolimus intermediate compound; the preparation method of the temsirolimus intermediate compound comprises the following steps: inert gas protection, adding the compound VI and the compound VII into the organic solvent A, adding organic alkali, performing temperature control reaction, detecting by TLC, adding the solvent B for dilution after the reaction is finished, drying by anhydrous sodium sulfate, and concentrating under reduced pressure to obtain the compound I. Provides a novel temsirolimus intermediate compound I; the temsirolimus prepared by the compound can effectively avoid the generation of byproducts, and the synthesized intermediate does not generate new impurities, so that the reaction is quicker, the method is economical and environment-friendly, the yield is higher, and the method is suitable for industrial production.

Description

Temsirolimus intermediate compounds
Technical Field
The invention belongs to the technical field of chemical synthesis, and particularly relates to a temsirolimus intermediate compound.
Background
Temsirolimus (temsirolimus), a derivative of sirolimus, under the chemical name sirolimus 42- [ 3-hydroxy-2- (hydroxymethyl) -2-methylpropionate ],) developed by the american wheatstone pharmaceutical company, is the first product of mTOR inhibitors to be applied for the treatment of cancer, was approved by the FDA for the treatment of advanced renal cell carcinoma in month 5 of 2007, and is the only drug currently capable of significantly prolonging the survival of renal cancer patients. The structural formula of temsirolimus is as follows:
the method comprises the following steps: the synthesis of temsirolimus was first reported in U.S. patent No. 5362718, the route is as follows:
The synthesis method has the defects that the reaction is not regioselective, 28-hydroxy and 40-hydroxy of rapamycin of tamsulosin Mo Sishi are easy to esterify, and the separation and purification of the product are difficult.
The second method is as follows: the synthetic route for temsirolimus reported in US2005234086 is as follows:
although the yield is higher than that of the first method, the method has regioselectivity of active hydroxyl at 31 position and 42 position, impurities and byproducts can be produced, and the production cost is greatly improved by adopting enzyme catalysis, so that the method is not beneficial to industrial production.
Therefore, the synthesis of temsirolimus still needs to explore a process route which has high regioselectivity, simple and convenient operation, shorter production period and higher yield and is more suitable for industrial production.
Disclosure of Invention
Aiming at the problems of the existing temsirolimus preparation technology, the invention provides a novel temsirolimus intermediate compound and a novel route for synthesizing temsirolimus by utilizing the intermediate.
The specific technical scheme of the invention is as follows:
a temsirolimus intermediate compound is shown in a formula I, and has a structural formula as follows:
A preparation method of a temsirolimus intermediate compound I shown in a formula I, which comprises the following reaction formula:
the method specifically comprises the following steps:
Inert gas protection, adding the compound VI and the compound VII into the organic solvent A, adding organic alkali, performing temperature control reaction, detecting by TLC, adding the solvent B for dilution after the reaction is finished, drying by anhydrous sodium sulfate, and concentrating under reduced pressure to obtain the compound I.
Preferably, the organic base is selected from one or a combination of N, N-diisopropylethylamine, triethylamine, 2, 6-lutidine, 4-dimethylaminopyridine, N-methylmorpholine, and 4-dimethylaminopyridine is preferred.
Preferably, the organic solvent A is selected from one or a combination of dichloromethane, N-dimethylformamide, chloroform, tetrahydrofuran, toluene and dioxane, wherein dichloromethane is preferred.
Preferably, the molar ratio of the compound VII to the organic base is 1:3.0-6.0, preferably 1:4.0.
Preferably, the feeding mole ratio of the compound VII to the compound VI is 1:1.0-2.0, wherein 1:1.2 is preferred.
Preferably, the solvent B is one or a combination of dichloromethane, chloroform and ethyl acetate.
Preferably, the temperature is 0 to 10 ℃.
The use of the intermediate compound I for preparing temsirolimus.
Wherein compound VI is prepared as follows:
the compound IV and the organic alkali are dissolved in the organic solution C, the compound V is added, the temperature is controlled, TLC detection is carried out, anhydrous sodium sulfate is dried after the reaction is finished, the mixture is filtered and concentrated under reduced pressure, and the compound VI is obtained, wherein the synthetic route is as follows:
Preferably, the organic base is selected from one or a combination of N, N-diisopropylethylamine, triethylamine, pyridine, 4-dimethylaminopyridine, N-methylmorpholine, particularly preferably N, N-diisopropylethylamine.
Preferably, the organic solvent C is selected from one or a combination of dichloromethane, N-dimethylformamide, chloroform, tetrahydrofuran and toluene, wherein dichloromethane is preferred.
Preferably, the molar ratio of the compound V to the organic base is 1:1.0-4.0, preferably 1:2.0.
Preferably, the molar ratio of the compound V to the compound IV is 1:1-1.3, preferably 1:1.1.
Preferably, the addition temperature is 25 to 40 ℃, preferably 30 ℃.
Wherein compound IV is prepared as follows:
inert gas protection, adding the compound III and the compound II into an organic solvent D, adding an organic base at a controlled temperature, reacting at room temperature after the addition, detecting by TLC (thin layer chromatography), filtering after the reaction is finished, adjusting the PH to be between 6 and 7 by using 0.2M sulfuric acid, extracting by using ethyl acetate, combining organic phases, drying by using anhydrous sodium sulfate, filtering, concentrating under reduced pressure to obtain the compound IV, wherein the synthetic route is as follows:
Preferably, the organic base is selected from one or a combination of sodium hydride, sodium methoxide, potassium tert-butoxide, n-butyllithium and lithium diisopropylamide, wherein sodium hydride is preferred.
Preferably, the feeding mole ratio of the compound II to the compound III is 1:1.0-1.5, wherein 1:1.2 is preferred.
Preferably, the feeding mole ratio of the compound II to the organic base is 1:2-2.5, wherein 1:2.2 is preferred.
Preferably, the organic solvent D is one or a combination of dichloromethane, 1, 4-dioxane, acetonitrile, chloroform and tetrahydrofuran, wherein tetrahydrofuran is preferred.
Preferably, the temperature of the addition of the organic base is from-5 to 5℃and, of these, 0℃is particularly preferred.
The invention also provides a method for preparing temsirolimus by using the intermediate compound I, which comprises the following steps: adding the compound I into an organic solvent E, slowly adding acid, performing temperature control reaction, detecting by TLC, washing with saturated sodium bicarbonate solution and saturated saline water for three times after the reaction is finished, merging organic phases, drying, suction filtering, and concentrating under reduced pressure to obtain a target compound temsirolimus; the synthetic route is as follows:
preferably, the acid is selected from one or a combination of sulfuric acid, hydrochloric acid, sulfurous acid, phosphoric acid, particularly preferably sulfuric acid.
Preferably, the sulfuric acid concentration is 3mol/L.
Preferably, the organic solvent E is selected from one or a combination of dichloromethane, N-dimethylformamide, chloroform, tetrahydrofuran, toluene, wherein tetrahydrofuran is particularly preferred.
Preferably, the feed ratio of the compound I to the acid is as follows: 1:1.0 to 4.0, particularly preferably 1:2.0, g/mL.
Preferably, the temperature is between 0 and 10 ℃, preferably 5 ℃.
The invention has the technical effects that:
The invention provides a novel temsirolimus intermediate compound I; the temsirolimus prepared by the compound can effectively avoid the generation of byproducts, and the synthesized intermediate does not generate new impurities, so that the reaction is quicker, the method is economical and environment-friendly, the yield is higher, and the method is suitable for industrial production.
Detailed Description
The invention is further illustrated by the following examples, with the understanding that: the examples of the present invention are intended to be illustrative of the invention and not to be limiting of the invention, so that simple modifications to the invention which are based on the method of the invention are within the scope of the invention as claimed.
In the following examples, various processes and methods, which are not described in detail, are conventional methods well known in the art.
The structure of the temsirolimus intermediate compound I is confirmed:
1H-NMR(400MHz,DMSO-d6)δ：0.71(d,J＝6.6Hz,3H),0.77(d,J＝6.0Hz,3H),0.81(d,J＝6.0Hz,3H),0.87(d,J＝6.0Hz,3H),0.92(t,J＝4.0Hz,3H),0.96(d,J＝6.6Hz,3H),1.06(s,3H),1.09～1.17(m,2H),1.33～1.36(m,2H),1.41(s,3H),1.51～1.57(m,6H),1.65(s,3H),1.69(d,J＝4.2Hz,2H),1.73(s,3H),1.78(s,3H),1.80～1.86(m,4H),1.89～1.92(m,4H),1.95～2.03(m,3H),2.04～2.07(m,4H),2.09～2.11(m,4H),2.13～2.20(m,2H),2.23～2.26(t,J＝4.6Hz,2H),2.34～2.73(m,3H),3.10(s,3H),3.19(s,3H),3.16～3.29(m,5H),3.37～3.49(m,6H),3.62(d,J＝11.4Hz,1H),3.63～3.66(m,4H),3.69(dd,J＝12.4、10.2Hz,2H),3.93(d,J＝3.6Hz,1H),4.01～4.11(m,1H),4.14(dd,J＝12.4、10.2Hz,2H),4.22(brs,1H),4.35～4.47(m,1H),4.55(t,J＝4.5Hz,2H),4.58～4.62(m,4H),4.94(d,J＝3.6Hz,1H),4.96～5.07(m,1H),5.10(d,J＝10.2Hz,1H),5.31(d,J＝4.2Hz,1H),5.44(dd,J＝14.4、10.2Hz,1H),6.10～6.15(m,2H),6.22(t,J＝10.2Hz,1H),6.38(dd,J＝13.8、11.4Hz,1H),6.61(s,1H);
13CNMR(100MHz,DMSO-d6)δ：11.1,13.6,14.1,15.2,15.3,15.7,16.6,16.7,17.4,20.6,20.7,20.9,22.7,24.9,26.9,27.1,28.8,28.9,29.3,29.4,29.9,30.6,31.3,32.8,33.6,33.9,35.7,35.8,36.6,38.7,39.6,40.0,40.2,40.4,43.9,44.9,45.5,50.6,51.4,56.3,57.6,57.8,64.1,64.2,66.7,70.6,70.7,73.2,73.3,74.0,75.4,75.5,76.5,76.6,80.7,82.4,85.9,99.5,125.1,127.9,130.9,132.7,137.6,138.2,139.9,167.2,169.7,174.4,175.5,199.6,208.0,211.0.
ESI-HRMS：m/z＝1291.5625[M+H]+；
Compound IV
1H-NMR(400MHz,CDCl3)δ：0.98(t,J＝4.0Hz,3H),1.52(s,3H),1.76(d,2H),2.13～2.39(m,14H),3.61～3.70(m,6H),3.96～4.03(m,2H),4.68～4.77(m,4H),11.86(s,1H);
13CNMR(100MHz,CDCl3)δ：15.1,15.6,16.9,20.8,20.8,29.1,29.1,29.5,29.5,33.4,45.6,71.2,71.2,74.3,74.3,75.9,75.9,180.4.
ESI-HRMS：m/z＝395.3136[M+H]+；
Compound VI
1H-NMR(400MHz,CDCl3)δ：0.94(t,J＝4.0Hz,3H),1.37(s,3H),1.69(d,2H),1.77～1.84(m,4H),1.99～2.05(m,4H),2.17～2.22(m,4H),2.24～2.35(t,J＝4.2Hz,2H),3.63～3.71(m,6H),3.87～3.99(m,2H),4.55～4.62(m,4H),7.82(s,2H);
13CNMR(100MHz,CDCl3)δ：15.3,15.7,16.6,20.6,20.7,28.8,28.9,29.1,29.3,33.6,44.9,70.6,70.7,73.2,73.3,75.4,75.5,127.3,127.4,132.3,137.5,137.6,142.9,153.4,175.5.
ESI-HRMS：m/z＝602.4105[M+H]+；
Example 1
Synthesis of Compound IV:
under the protection of nitrogen, adding the compound III (28.14 g,0.21 mol) and the compound II (84.00 g,0.2 mol) into 45ml of tetrahydrofuran, controlling the temperature to be 0 ℃, adding sodium hydride (16.80 g,0.42 mol), heating to room temperature for reaction after the addition, detecting by TLC, filtering after the reaction is finished, adjusting the PH value to be between 6 and 7 by using 0.2M sulfuric acid, extracting by using ethyl acetate, merging organic phases, drying by using anhydrous sodium sulfate, filtering, concentrating under reduced pressure to obtain the compound IV, wherein the yield is 97.5 percent and the purity is 99.72 percent.
Example 2
Synthesis of Compound VI:
Compound IV (41.41 g,0.21 mol) and N, N-diisopropylethylamine (51.7 g,0.4 mol) were dissolved in 250mLDCM, compound V (48.76 g,0.20 mol) was added, the temperature was controlled at 30℃and TLC was checked, the reaction was completed, purified water was washed 3 times, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to give compound VI with a yield of 99.83% and a purity of 99.76%.
Example 3
Synthesis of Compound I:
Under the protection of nitrogen, compound VII (91.34 g,0.1 mol) and compound VI (72.22 g,0.12 mol) are added into 500mL of dichloromethane to be stirred and dissolved, 4-dimethylaminopyridine (48.86 g,0.40 mol) is added, the temperature is controlled to be 5 ℃ after dissolution, TLC detection is carried out, ethyl acetate is added for dilution after the reaction is finished, anhydrous sodium sulfate is dried, and the concentration is carried out under reduced pressure, so that the compound I is obtained, wherein the yield is 98.2%, and the purity is 99.92%.
Example 4
Under the protection of nitrogen, compound VII (45.67 g,0.05 mol) and compound VI (60.20 g,0.10 mol) are added into 500mLN, N-dimethylformamide and stirred for dissolution, N-diisopropylethylamine (51.7 g,0.40 mol) is added, after the dissolution is finished, the temperature is controlled to be 0 ℃, TLC detection is carried out, methylene chloride is added for dilution, anhydrous sodium sulfate is added for drying, and the concentration is carried out under reduced pressure, thus obtaining the compound I with the yield of 95.5% and the purity of 99.89%.
Example 5
Under the protection of nitrogen, adding compound VII (45.67 g,0.05 mol) and compound VI (120.36 g,0.20 mol) into 600mL of chloroform, stirring for dissolution, adding triethylamine (202.38 g,0.40 mol), controlling the temperature to 10 ℃ after dissolution, detecting by TLC, adding chloroform for dilution after the reaction, drying with anhydrous sodium sulfate, concentrating under reduced pressure to obtain compound I with the yield of 95.4% and the purity of 99.82%.
Example 6
Under the protection of nitrogen, compound VII (91.34 g,0.10 mol) and compound VI (48.14 g,0.08 mol) are added into 550mL of tetrahydrofuran for stirring and dissolution, 2, 6-lutidine (42.86 g,0.40 mol) is added, the temperature is controlled to be 5 ℃ after dissolution, TLC detection is carried out, ethyl acetate is added for dilution after the reaction is finished, anhydrous sodium sulfate is dried, and the compound I is obtained after decompression concentration, the yield is 93.2%, and the purity is 99.78%.
Example 7
Under the protection of nitrogen, compound VII (91.34 g,0.10 mol) and compound VI (144.44 g,0.24 mol) are added into 500mL of toluene for stirring and dissolution, N-methylmorpholine (40.46 g,0.40 mol) is added, the temperature is controlled to 8 ℃ after dissolution, TLC detection is carried out, ethyl acetate is added for dilution after the reaction is finished, anhydrous sodium sulfate is dried, and the obtained product is concentrated under reduced pressure, thus obtaining compound I with the yield of 92.6% and the purity of 99.74%.
Example 8
Under the protection of nitrogen, adding the compound VII (91.34 g,0.10 mol) and the compound VI (72.22 g,0.12 mol) into 600mL of dioxane, stirring for dissolution, adding 4-dimethylaminopyridine (36.64 g,0.30 mol), controlling the temperature to 5 ℃ after dissolution, performing TLC detection, adding chloroform for dilution after the reaction is finished, drying with anhydrous sodium sulfate, concentrating under reduced pressure to obtain the compound I, wherein the yield is 96.6%, and the purity is 99.83%.
Example 9
Under the protection of nitrogen, compound VII (91.34 g,0.10 mol) and compound VI (72.22 g,0.12 mol) are added into 500mLN, N-dimethylformamide to be stirred and dissolved, 4-dimethylaminopyridine (73.3 g,0.60 mol) is added, after the dissolution is finished, the temperature is controlled to 5 ℃, TLC detection is carried out, ethyl acetate is added for dilution, anhydrous sodium sulfate is added for drying, and the concentration is carried out under reduced pressure, thus obtaining the compound I with the yield of 96.5% and the purity of 99.81%.
Example 10
Under the protection of nitrogen, adding compound VII (91.34 g,0.10 mol) and compound VI (72.22 g,0.12 mol) into 550mL of chloroform, stirring for dissolution, adding 4-dimethylaminopyridine (24.42 g,0.20 mol), controlling the temperature to 10 ℃ after dissolution, performing TLC detection, adding ethyl acetate for dilution after the reaction, drying with anhydrous sodium sulfate, concentrating under reduced pressure to obtain compound I, wherein the yield is 96.0% and the purity is 99.82%.
Example 11
Under the protection of nitrogen, adding compound VII (91.34 g,0.10 mol) and compound VI (72.22 g,0.12 mol) into 600mL of tetrahydrofuran, stirring for dissolution, adding 4-dimethylaminopyridine (85.5 g,0.70 mol), controlling the temperature to 5 ℃ after dissolution, detecting by TLC, adding methylene dichloride for dilution after the reaction is finished, drying by anhydrous sodium sulfate, and concentrating under reduced pressure to obtain the compound I with the yield of 96.2% and the purity of 99.76%.
Example 12
Compound I (12.90 g,0.01 mol) was added to tetrahydrofuran, 3mol/L sulfuric acid (26 mL) was slowly added, the reaction was performed at 5 ℃ under controlled temperature, TLC detection was performed, saturated sodium bicarbonate solution and saturated brine were washed three times after the reaction was completed, the organic phases were combined, dried, suction filtered, and concentrated under reduced pressure to obtain the target compound temsirolimus, yield 94.2%, purity 99.80%.

Claims (8)

1. A temsirolimus intermediate compound is shown in a formula I, and has a structural formula as follows:
。
2. A process for preparing temsirolimus intermediate compound I as claimed in claim 1, wherein compound VI is reacted with compound VII to give intermediate compound I of the formula:
。
3. The preparation method of the temsirolimus intermediate compound I according to claim 2, which is characterized by comprising the following steps: inert gas protection, adding the compound VI and the compound VII into an organic solvent A, adding organic alkali, performing temperature control reaction, detecting by TLC, adding a solvent B for dilution after the reaction is finished, drying by anhydrous sodium sulfate, and concentrating under reduced pressure to obtain a compound I; wherein the organic solvent A is selected from one or a combination of dichloromethane, N-dimethylformamide, chloroform, tetrahydrofuran, toluene and dioxane; the solvent B is one or the combination of dichloromethane, chloroform and ethyl acetate.
4. The method according to claim 3, wherein the organic base is selected from one or a combination of N, N-diisopropylethylamine, triethylamine, 2, 6-lutidine, 4-dimethylaminopyridine and N-methylmorpholine.
5. The process according to claim 3, wherein the molar ratio of the compound VII to the organic base is 1:3.0 to 6.0.
6. The process according to claim 3, wherein the molar ratio of the compound VII to the compound VI is 1:1.0 to 2.0.
7. The process according to claim 3, wherein the temperature of the reaction is controlled to 0 to 10 ℃.
8. Use of intermediate compound I according to claim 1 for the preparation of temsirolimus.
CN202010743121.0A 2020-07-29 2020-07-29 Temsirolimus intermediate compounds Active CN114057792B (en)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113372375A (en) * 2020-03-10 2021-09-10 鲁南制药集团股份有限公司 Preparation method of temsirolimus intermediate
CN114057767A (en) * 2020-07-29 2022-02-18 鲁南制药集团股份有限公司 Preparation method of temsirolimus

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CN107561170B (en) * 2016-07-02 2021-07-30 山东新时代药业有限公司 Analysis and detection method of temsirolimus intermediate

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Publication number Priority date Publication date Assignee Title
CN113372375A (en) * 2020-03-10 2021-09-10 鲁南制药集团股份有限公司 Preparation method of temsirolimus intermediate
CN114057767A (en) * 2020-07-29 2022-02-18 鲁南制药集团股份有限公司 Preparation method of temsirolimus

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