CN113372325A - Temsirolimus intermediate compound III - Google Patents
Temsirolimus intermediate compound III Download PDFInfo
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- CN113372325A CN113372325A CN202010160909.9A CN202010160909A CN113372325A CN 113372325 A CN113372325 A CN 113372325A CN 202010160909 A CN202010160909 A CN 202010160909A CN 113372325 A CN113372325 A CN 113372325A
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- Prior art keywords
- compound
- temsirolimus
- compound iii
- organic base
- side chain
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- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 title claims abstract description 42
- CBPNZQVSJQDFBE-FUXHJELOSA-N Temsirolimus Chemical compound C1C[C@@H](OC(=O)C(C)(CO)CO)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 CBPNZQVSJQDFBE-FUXHJELOSA-N 0.000 title claims abstract description 29
- 229960000235 temsirolimus Drugs 0.000 title claims abstract description 24
- QFJCIRLUMZQUOT-UHFFFAOYSA-N temsirolimus Natural products C1CC(O)C(OC)CC1CC(C)C1OC(=O)C2CCCCN2C(=O)C(=O)C(O)(O2)C(C)CCC2CC(OC)C(C)=CC=CC=CC(C)CC(C)C(=O)C(OC)C(O)C(C)=CC(C)C(=O)C1 QFJCIRLUMZQUOT-UHFFFAOYSA-N 0.000 title claims abstract description 24
- QFJCIRLUMZQUOT-HPLJOQBZSA-N sirolimus Chemical compound C1C[C@@H](O)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 QFJCIRLUMZQUOT-HPLJOQBZSA-N 0.000 claims abstract description 35
- ZAHRKKWIAAJSAO-UHFFFAOYSA-N rapamycin Natural products COCC(O)C(=C/C(C)C(=O)CC(OC(=O)C1CCCCN1C(=O)C(=O)C2(O)OC(CC(OC)C(=CC=CC=CC(C)CC(C)C(=O)C)C)CCC2C)C(C)CC3CCC(O)C(C3)OC)C ZAHRKKWIAAJSAO-UHFFFAOYSA-N 0.000 claims abstract description 34
- 229960002930 sirolimus Drugs 0.000 claims abstract description 34
- 238000003756 stirring Methods 0.000 claims abstract description 29
- 238000006243 chemical reaction Methods 0.000 claims abstract description 24
- 238000000034 method Methods 0.000 claims abstract description 18
- 150000007530 organic bases Chemical class 0.000 claims abstract description 15
- WZEWDEAIHCUMKY-UHFFFAOYSA-N 2,2,5-trimethyl-1,3-dioxane-5-carboxylic acid Chemical compound CC1(C)OCC(C)(C(O)=O)CO1 WZEWDEAIHCUMKY-UHFFFAOYSA-N 0.000 claims abstract description 13
- 238000001816 cooling Methods 0.000 claims abstract description 11
- 238000002360 preparation method Methods 0.000 claims abstract description 11
- FTVLMFQEYACZNP-UHFFFAOYSA-N trimethylsilyl trifluoromethanesulfonate Chemical compound C[Si](C)(C)OS(=O)(=O)C(F)(F)F FTVLMFQEYACZNP-UHFFFAOYSA-N 0.000 claims abstract description 10
- 239000003960 organic solvent Substances 0.000 claims abstract description 8
- 239000011261 inert gas Substances 0.000 claims abstract description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 66
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 33
- 150000001875 compounds Chemical class 0.000 claims description 24
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-diisopropylethylamine Substances CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 20
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 16
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 15
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 14
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 12
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 claims description 9
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 claims description 9
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 7
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 6
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 claims description 4
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 3
- XWKFPIODWVPXLX-UHFFFAOYSA-N 2-methyl-5-methylpyridine Natural products CC1=CC=C(C)N=C1 XWKFPIODWVPXLX-UHFFFAOYSA-N 0.000 claims description 2
- 238000009776 industrial production Methods 0.000 abstract description 6
- 239000012535 impurity Substances 0.000 abstract description 4
- 238000005886 esterification reaction Methods 0.000 abstract description 3
- 239000000126 substance Substances 0.000 abstract description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N ethyl acetate Substances CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 38
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 34
- 239000012074 organic phase Substances 0.000 description 27
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 20
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 20
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 18
- 238000001035 drying Methods 0.000 description 18
- 238000004128 high performance liquid chromatography Methods 0.000 description 17
- 229910052757 nitrogen Inorganic materials 0.000 description 17
- 239000000243 solution Substances 0.000 description 14
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 11
- 238000004440 column chromatography Methods 0.000 description 10
- 239000008367 deionised water Substances 0.000 description 10
- 229910021641 deionized water Inorganic materials 0.000 description 10
- 239000003480 eluent Substances 0.000 description 10
- 239000003208 petroleum Substances 0.000 description 10
- 238000005406 washing Methods 0.000 description 10
- 229960001701 chloroform Drugs 0.000 description 9
- 238000000605 extraction Methods 0.000 description 9
- 239000008213 purified water Substances 0.000 description 9
- 239000008346 aqueous phase Substances 0.000 description 8
- 238000001914 filtration Methods 0.000 description 8
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 7
- 239000012295 chemical reaction liquid Substances 0.000 description 7
- 125000006239 protecting group Chemical group 0.000 description 7
- 239000000203 mixture Substances 0.000 description 6
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
- HXITXNWTGFUOAU-UHFFFAOYSA-N phenylboronic acid Chemical compound OB(O)C1=CC=CC=C1 HXITXNWTGFUOAU-UHFFFAOYSA-N 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 3
- 230000002194 synthesizing effect Effects 0.000 description 3
- PTBDIHRZYDMNKB-UHFFFAOYSA-N 2,2-Bis(hydroxymethyl)propionic acid Chemical compound OCC(C)(CO)C(O)=O PTBDIHRZYDMNKB-UHFFFAOYSA-N 0.000 description 2
- OZGSEIVTQLXWRO-UHFFFAOYSA-N 2,4,6-trichlorobenzoyl chloride Chemical compound ClC(=O)C1=C(Cl)C=C(Cl)C=C1Cl OZGSEIVTQLXWRO-UHFFFAOYSA-N 0.000 description 2
- SVTBMSDMJJWYQN-UHFFFAOYSA-N 2-methylpentane-2,4-diol Chemical compound CC(O)CC(C)(C)O SVTBMSDMJJWYQN-UHFFFAOYSA-N 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 238000006555 catalytic reaction Methods 0.000 description 2
- 230000007613 environmental effect Effects 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- RMGHERXMTMUMMV-UHFFFAOYSA-N 2-methoxypropane Chemical compound COC(C)C RMGHERXMTMUMMV-UHFFFAOYSA-N 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 208000006265 Renal cell carcinoma Diseases 0.000 description 1
- 150000008065 acid anhydrides Chemical class 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000004519 grease Substances 0.000 description 1
- 231100000086 high toxicity Toxicity 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 1
- 229940124302 mTOR inhibitor Drugs 0.000 description 1
- 239000003628 mammalian target of rapamycin inhibitor Substances 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 229920001296 polysiloxane Polymers 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- -1 temsirolimus side chain compound Chemical class 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D319/00—Heterocyclic compounds containing six-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D319/04—1,3-Dioxanes; Hydrogenated 1,3-dioxanes
- C07D319/06—1,3-Dioxanes; Hydrogenated 1,3-dioxanes not condensed with other rings
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention belongs to the field of pharmaceutical chemicals, and particularly relates to a temsirolimus intermediate compound III. The preparation method of the temsirolimus side chain compound III provided by the invention comprises the following steps: under the protection of inert gas, adding 2,2, 5-trimethyl-1, 3-dioxane-5-carboxylic acid into an organic solvent for dissolving, cooling, adding organic base, adding trimethylsilyl trifluoromethanesulfonate, and stirring at room temperature for reaction to obtain a temsirolimus side chain compound III. The intermediate compound III provided by the invention is used for preparing temsirolimus, so that the regioselectivity of rapamycin esterification reaction can be effectively improved, no new impurity is generated, and the method is suitable for industrial production.
Description
Technical Field
The invention belongs to the field of pharmaceutical chemicals, and particularly relates to a temsirolimus intermediate compound III.
Background
Temsirolimus (temsirolimus), a derivative of sirolimus, chemically named sirolimus 42- [ 3-hydroxy-2- (hydroxymethyl) -2-methylpropionate ], was the first product applied for treating cancers in mTOR inhibitor drugs, developed by american hui pharmaceutical company, and approved by FDA through a fast approval channel for the treatment of advanced renal cell carcinoma at 5 months 2007, and has the following structural formula:
most of the prior process routes take rapamycin as a main raw material, ester is formed by rapamycin and different side chain protecting groups, and then the protecting groups are removed to obtain temsirolimus, wherein the following reactions are mainly carried out according to the difference of the side chain protecting groups:
the method comprises the following steps: U.S. Pat. Nos. 5,5362718, 6,77983 and 3,9018373 report the reaction of 2, 2-dimethylolpropionic acid protected by 2, 2-methoxypropane and mixed anhydride generated by 2,4, 6-trichlorobenzoyl chloride to form ester as side chain group by using sirolimus or 31-O-trimethylsilylether of sirolimus as raw material, and then hydrolyzing under acidic condition to obtain temsirolimus, 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%.
The second method comprises the following steps: U.S. patent application 2005033046 uses phenylboronic acid to protect 2, 2-dimethylolpropionic acid, uses mixed acid anhydride generated by 2,4, 6-trichlorobenzoyl chloride as a side chain group, and generates ester-forming reaction with sirolimus or sirolimus 31-O-trimethylsilyl ether, and finally uses 2-methyl-2, 4-pentanediol for deprotection to obtain temsirolimus, wherein the route is as follows:
the method adopts high-toxicity phenylboronic acid as a side chain protecting group, is expensive, does not meet the requirement of environmental protection, and is not beneficial to industrial production.
The third method comprises the following steps: in the US2005234086 patent, 2-hydroxymethyl allyl propionate protected by alkyl is taken as a side chain group, reacts with sirolimus under the catalysis of enzyme, and is deprotected to obtain temsirolimus, and the synthetic route is as follows:
although the method has high yield, the regioselectivity of 31-position active hydroxyl and 42-position active hydroxyl exists, 31-esterification impurities and 31, 42-diester byproducts are generated, and the production cost is greatly increased due to enzyme catalysis, so that the method is not beneficial to industrial production.
Therefore, the problem to be solved at present is to explore a process route for synthesizing the side chain protecting group of 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 the side chain protecting group of temsirolimus in the prior art, the invention provides a novel compound for the side chain protecting group of temsirolimus 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 side chain compound represented by formula III:
a preparation method of temsirolimus side chain compound III comprises the following steps: under the protection of inert gas, adding a compound I, namely 2,2, 5-trimethyl-1, 3-dioxane-5-carboxylic acid into an organic solvent for dissolving, cooling, adding an organic base, adding a compound II, namely trimethylsilyl trifluoromethanesulfonate, and stirring at room temperature for reacting to obtain a temsirolimus side chain compound III, wherein the reaction route is as follows:
preferably, the organic base may be selected from one or a combination of triethylamine, pyridine, 2, 6-lutidine, N-diisopropylethylamine, and triethylamine is particularly preferred.
In a preferable embodiment, the feeding molar ratio of the compound I, the compound II and the organic base is 1: 1.0-1.5: 1.2-2.5, and particularly preferably 1:1.1: 1.5.
Preferably, the organic solvent is one or a combination of dichloromethane, N-dimethylformamide, acetonitrile, chloroform and tetrahydrofuran, wherein dichloromethane is particularly preferred.
In a preferable scheme, the temperature of the added organic base is-10 ℃, and particularly preferably 0 ℃.
In a preferred embodiment, after the reaction is finished, a post-treatment operation is required, specifically: after the reaction is finished, adding deionized water (the volume ratio of the solvent to the deionized water is 1:1) into the reaction solution, stirring and crystallizing to obtain a side chain compound III; the crystallization temperature is-5 to 5 ℃.
The use of compound III for the preparation of temsirolimus.
The application of the compound III in preparing an important intermediate compound V of temsirolimus, namely 2,2, 5-trimethyl-1, 3-dioxane-5-carboxylic acid sirolimus 31-O-trimethylsilylether-42-ester, comprises the following steps: dissolving mono-protected sirolimus, namely a compound IV and organic base in an organic solution, adding a side chain compound III at controlled temperature, and reacting at room temperature to obtain an intermediate compound V, 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 and N-methylmorpholine, and N, N-diisopropylethylamine is particularly preferred.
Preferably, the organic solvent is selected from one or a combination of dichloromethane, N-dimethylformamide, chloroform, tetrahydrofuran and toluene, wherein dichloromethane is particularly preferred.
Preferably, the feeding molar ratio of the compound IV, the organic base and the compound III is as follows: 1: 4.0-7.0: 2.0-4.0, and particularly preferably 1:6.0: 2.5.
In a preferred scheme, the temperature of adding the side chain compound III is-10 ℃, and preferably 0 ℃.
In a preferred embodiment, after the reaction is finished, a post-treatment operation is required, specifically: TLC detecting reaction, adding purified water into the reaction solution, extracting with organic solvent, mixing organic phases, washing with sodium bicarbonate solution and saturated saline solution, drying with anhydrous sodium sulfate, concentrating under reduced pressure, and separating by column chromatography (eluent V)Petroleum ether：VEthyl acetate2: 1); the extraction solvent is one or the combination of dichloromethane, trichloromethane and ethyl acetate.
Compared with the prior art, the invention has the following technical effects:
1. provides a new temsirolimus intermediate compound III and a new method for preparing an important temsirolimus intermediate by using the compound simply, conveniently and efficiently, the whole synthesis method has simple and convenient operation, high reaction yield and high purity of the obtained product;
2. the intermediate compound III provided by the invention for preparing temsirolimus can effectively improve the regioselectivity of rapamycin esterification reaction and effectively prevent the generation of new impurities.
In conclusion, the invention provides a novel compound and a novel method for synthesizing an important temsirolimus intermediate 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 method is economic 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. 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:
structural characterization of Compound III
High resolution mass spectrum of compound III: ESI-HRMS: 307.0420[ M + H ] M/z]+；1H-NMR(400MHz,CDCl3)：4.08～4.17(d,J＝8.6Hz,2H)，3.79～3.85(d,J＝8.4Hz,2H)，1.56(s,3H)，1.29(s,6H)；13C NMR(100MHz,CDCl3)：δ178.4,118.3,114.8,69.6,69.4,42.5,26.8,26.7,16.2.
Example 1
Under the protection of nitrogen, adding 2,2, 5-trimethyl-1, 3-dioxane-5-carboxylic acid (17.42g, 0.1mol) into 120mL of dichloromethane, stirring and dissolving, cooling the system to 0 ℃ after dissolving, adding triethylamine (15.18g, 0.15mol), controlling the temperature to 0 ℃, dropwise adding trimethylsilyl trifluoromethanesulfonate (24.45g, 0.11mol), stirring and reacting at room temperature, adding 120mL of deionized water into the reaction liquid after the reaction is finished, adding 120mL of dichloromethane for extraction, drying the organic phase with anhydrous sodium sulfate, filtering, and concentrating under reduced pressure to obtain the compound III, wherein the yield is 98.7%, and the HPLC purity is 99.88%.
Example 2
Under the protection of nitrogen, adding 2,2, 5-trimethyl-1, 3-dioxane-5-carboxylic acid (17.42g, 0.1mol) into 120mL of trichloromethane, stirring and dissolving, cooling the system to 10 ℃ after dissolving, adding triethylamine (12.14g, 0.12mol), controlling the temperature to 10 ℃, dropwise adding trimethylsilyl trifluoromethanesulfonate (24.45g, 0.11mol), stirring and reacting at room temperature, adding 120mL of deionized water into the reaction liquid after the reaction is finished, adding 120mL of trichloromethane for extraction, drying the organic phase with anhydrous sodium sulfate, filtering, and concentrating under reduced pressure to obtain a compound III, wherein the yield is 96.2% and the HPLC purity is 99.82%.
Example 3
Under the protection of nitrogen, adding 2,2, 5-trimethyl-1, 3-dioxane-5-carboxylic acid (17.42g, 0.1mol) into 120mLN, N-dimethylformamide, stirring and dissolving, cooling the system to-10 ℃ after dissolving, adding triethylamine (25.30g, 0.25mol), controlling the temperature to-10 ℃, dropwise adding trimethylsilyl trifluoromethanesulfonate (24.45g, 0.11mol), stirring and reacting at room temperature after completing the dropwise addition, adding 120mL of deionized water into reaction liquid, adding 120mL of ethyl acetate for extraction, drying an organic phase by using anhydrous sodium sulfate, filtering, and concentrating under reduced pressure to obtain a compound III, wherein the yield is 95.1%, and the HPLC purity is 99.78%.
Example 4
Under the protection of nitrogen, adding 2,2, 5-trimethyl-1, 3-dioxane-5-carboxylic acid (17.42g, 0.1mol) into 120mL acetonitrile, stirring and dissolving, cooling the system to-15 ℃ after dissolving, adding triethylamine (10.12g, 0.1mol), controlling the temperature to-15 ℃, dropwise adding trifluoromethanesulfonic acid trimethyl silicone grease (24.45g, 0.11mol), stirring and reacting at room temperature, adding 120mL deionized water into the reaction liquid after the reaction is finished, adding 120mL dichloromethane for extraction, drying the organic phase with anhydrous sodium sulfate, filtering, and concentrating under reduced pressure to obtain a compound III, wherein the yield is 92.7% and the HPLC purity is 99.71%.
Example 5
Under the protection of nitrogen, adding 2,2, 5-trimethyl-1, 3-dioxane-5-carboxylic acid (17.42g, 0.1mol) into 120mL acetonitrile, stirring and dissolving, cooling the system to-5 ℃ after dissolving, adding triethylamine (27.32g, 0.27mol), controlling the temperature to-5 ℃, dropwise adding trimethylsilyl trifluoromethanesulfonate (24.45g, 0.11mol), stirring and reacting at room temperature, adding 120mL deionized water into the reaction liquid after the reaction is finished, adding 120mL ethyl acetate for extraction, drying the organic phase with anhydrous sodium sulfate, filtering, and concentrating under reduced pressure to obtain a compound III, wherein the yield is 92.1% and the HPLC purity is 99.68%.
Example 6
Under the protection of nitrogen, adding 2,2, 5-trimethyl-1, 3-dioxane-5-carboxylic acid (17.42g, 0.1mol) into 120mL of dichloromethane, stirring and dissolving, cooling the system to 0 ℃ after dissolving, adding pyridine (11.87g, 0.15mol), controlling the temperature to 0 ℃, dropwise adding trimethylsilyl trifluoromethanesulfonate (22.23g, 0.1mol), stirring and reacting at room temperature, adding 120mL of deionized water into the reaction liquid after the reaction is finished, adding 120mL of ethyl acetate for extraction, drying the organic phase with anhydrous sodium sulfate, filtering, and concentrating under reduced pressure to obtain a compound III, wherein the yield is 94.3% and the HPLC purity is 99.81%.
Example 7
Under the protection of nitrogen, adding 2,2, 5-trimethyl-1, 3-dioxane-5-carboxylic acid (17.42g, 0.1mol) into 120mL tetrahydrofuran, stirring and dissolving, cooling the system to 0 ℃ after dissolving, adding 2, 6-dimethylpyridine (16.07g, 0.15mol), controlling the temperature to 0 ℃, dropwise adding trimethylsilyl trifluoromethanesulfonate (33.34g, 0.15mol), stirring and reacting at room temperature after completing the dropwise addition, adding 120mL deionized water into the reaction solution, adding 120mL ethyl acetate for extraction, drying the organic phase with anhydrous sodium sulfate, filtering, and concentrating under reduced pressure to obtain a compound III with the yield of 95.1% and the HPLC purity of 99.76%.
Example 8
Under the protection of nitrogen, adding 2,2, 5-trimethyl-1, 3-dioxane-5-carboxylic acid (17.42g, 0.1mol) into 120mL tetrahydrofuran, stirring and dissolving, cooling the system to 15 ℃ after dissolving, adding N, N-diisopropylethylamine (16.07g, 0.15mol), controlling the temperature to 15 ℃, dropwise adding trimethylsilyl trifluoromethanesulfonate (37.78g, 0.17mol), stirring at room temperature for reaction after completing the dropwise addition, adding 120mL deionized water into the reaction liquid, adding 120mL ethyl acetate for extraction, drying the organic phase with anhydrous sodium sulfate, filtering, and concentrating under reduced pressure to obtain a compound III with the yield of 86.5% and the HPLC purity of 99.70%.
Preparation of Compound V
Example 9
Under the protection of nitrogen, adding sirolimus 31-O-trimethylsilyl ether (98.56g, 0.1mol) and N, N-diisopropylethylamine (77.55g, 0.6mol) into 1L dichloromethane, stirring at room temperature to dissolve, controlling the temperature to be 0 ℃, adding side chain compound III (76.51g, 0.25mol), reacting at room temperature until the mono-protected sirolimus is completely reacted, adding purified water (1L), extracting an aqueous phase with dichloromethane (500mL multiplied by 2), combining organic phases, washing the organic phase with saturated sodium bicarbonate solution and saturated saline solution in sequence, drying with anhydrous sodium sulfate, concentrating under reduced pressure to dryness, and separating by column chromatography (eluent V)Petroleum ether：VEthyl acetate2:1) compound V was obtained in 98.8% yield and 99.87% HPLC purity.
Example 10
Under the protection of nitrogen, adding sirolimus 31-O-trimethylsilyl ether (98.56g, 0.1mol) and N, N-diisopropylethylamine (51.70g, 0.4mol) into 1LN, N-dimethylformamide, stirring at room temperature to dissolve, controlling the temperature to be-10 ℃, adding side chain compound III (76.51g, 0.25mol), reacting at room temperature until the single-protection sirolimus is completely reacted, adding purified water (1L) into the mixture, and extracting water with dichloromethane (500mL multiplied by 2)Combining the phases, washing the organic phase with saturated sodium bicarbonate solution and saturated brine, drying over anhydrous sodium sulfate, concentrating under reduced pressure to dryness, and separating by column chromatography (eluent V)Petroleum ether：VEthyl acetate2:1) compound V was obtained in 95.3% yield and 99.82% HPLC purity.
Example 11
Under the protection of nitrogen, adding sirolimus 31-O-trimethylsilyl ether (98.56g, 0.1mol) and N, N-diisopropylethylamine (90.47g, 0.7mol) into 1L acetonitrile, stirring at room temperature to dissolve, controlling the temperature to 10 ℃, adding side chain compound III (76.51g, 0.25mol), reacting at room temperature until the mono-protected sirolimus is completely reacted, adding purified water (1L) into the mixture, extracting an aqueous phase with trichloromethane (500mL multiplied by 2), combining the organic phases, washing the organic phase with saturated sodium bicarbonate solution and saturated saline solution in sequence, drying the mixture with anhydrous sodium sulfate, concentrating the mixture under reduced pressure to dryness, and separating by column chromatography (eluent V)Petroleum ether：VEthyl acetate2:1) compound V was obtained in 94.6% yield and 99.76% HPLC purity.
Example 12
Under the protection of nitrogen, adding sirolimus 31-O-trimethylsilyl ether (98.56g, 0.1mol) and N, N-diisopropylethylamine (45.23g, 0.35mol) into 1L tetrahydrofuran, stirring at room temperature to dissolve, controlling the temperature to 15 ℃, adding side chain compound III (76.51g, 0.25mol), reacting at room temperature until the mono-protected sirolimus is completely reacted, adding purified water (1L) into the mixture, extracting an aqueous phase with trichloromethane (500mL multiplied by 2), combining the organic phases, washing the organic phase with saturated sodium bicarbonate solution and saturated saline solution in sequence, drying the organic phase with anhydrous sodium sulfate, concentrating the mixture under reduced pressure to dryness, and separating by column chromatography (eluent V)Petroleum ether：VEthyl acetate2:1) compound V was obtained in 86.6% yield with an HPLC purity of 99.72%.
Example 13
Under the protection of nitrogen, adding sirolimus 31-O-trimethylsilyl ether (98.56g, 0.1mol) and N, N-diisopropylethylamine (96.93g, 0.75mol) into 1L of trichloromethane, stirring at room temperature to dissolve, controlling the temperature to be-15 ℃, adding side chain compound III (76.51g, 0.25mol), reacting at room temperature until all the mono-protected sirolimus is reacted, and adding purified water (A), (B), (C), (1L), extracting the aqueous phase with chloroform (500 mL. times.2), combining the organic phases, washing the organic phases successively with saturated sodium bicarbonate solution and saturated brine, drying over anhydrous sodium sulfate, concentrating under reduced pressure to dryness, and separating by column chromatography (eluent V)Petroleum ether：VEthyl acetate2:1) compound V was obtained in 84.8% yield and 99.68% HPLC purity.
Example 14
Under the protection of nitrogen, adding sirolimus 31-O-trimethylsilyl ether (98.56g, 0.1mol) and triethylamine (60.72g, 0.6mol) into 1L dichloromethane, stirring at room temperature to dissolve, controlling the temperature to 0 ℃, adding side chain compound III (61.21g, 0.2mol), reacting at room temperature until all the single-protection sirolimus reacts, adding purified water (1L), extracting an aqueous phase with dichloromethane (500mL multiplied by 2), combining organic phases, washing the organic phase with a saturated sodium bicarbonate solution and a saturated saline solution in sequence, drying with anhydrous sodium sulfate, concentrating under reduced pressure to dryness, and separating by column chromatography (eluent V)Petroleum ether：VEthyl acetate2:1) compound V was obtained in 94.8% yield and 99.83% HPLC purity.
Example 15
Under the protection of nitrogen, adding sirolimus 31-O-trimethylsilyl ether (98.56g, 0.1mol) and pyridine (47.46g, 0.6mol) into 1L dichloromethane, stirring at room temperature to dissolve, controlling the temperature to be-5 ℃, adding side chain compound III (122.42g, 0.4mol), reacting at room temperature until all the single-protection sirolimus reacts, adding purified water (1L), extracting an aqueous phase by dichloromethane (500mL multiplied by 2), combining organic phases, washing the organic phase by saturated sodium bicarbonate solution and saturated saline in sequence, drying by anhydrous sodium sulfate, concentrating under reduced pressure to dryness, and separating by column chromatography (eluent V)Petroleum ether：VEthyl acetate2:1) compound V was obtained in 95.4% yield and 99.77% HPLC purity.
Example 16
Under the protection of nitrogen, adding sirolimus 31-O-trimethylsilyl ether (98.56g, 0.1mol) and 4-dimethylamino pyridine (73.30g, 0.6mol) into 1L dichloromethane, stirring at room temperature to dissolve, controlling the temperature to be 0 ℃, adding a side chain compound III (55.09g, 0.18mol), reacting at room temperature until all the mono-protected sirolimus is reacted, and adding purified sirolimus into the mixtureWater (1L), extracting the aqueous phase with dichloromethane (500 mL. times.2), combining the organic phases, washing the organic phases successively with saturated sodium bicarbonate solution and saturated brine, drying over anhydrous sodium sulfate, concentrating to dryness under reduced pressure, and separating by column chromatography (eluent V)Petroleum ether：VEthyl acetate2:1) compound V was obtained in 85.3% yield and 99.75% HPLC purity.
Example 17
Under the protection of nitrogen, adding sirolimus 31-O-trimethylsilyl ether (98.56g, 0.1mol) and N-methylmorpholine (60.69g, 0.6mol) into 1L dichloromethane, stirring at room temperature to dissolve, controlling the temperature to be 0 ℃, adding side chain compound III (128.54g, 0.42mol), reacting at room temperature until all the mono-protected sirolimus is reacted, adding purified water (1L), extracting an aqueous phase with dichloromethane (500mL multiplied by 2), combining organic phases, washing the organic phase with saturated sodium bicarbonate solution and saturated saline solution in sequence, drying with anhydrous sodium sulfate, concentrating under reduced pressure to dryness, and separating by column chromatography (eluent V)Petroleum ether：VEthyl acetate2:1) compound V was obtained in 84.5% yield with HPLC purity 99.68%.
Claims (10)
1. A temsirolimus intermediate compound represented by formula III:
2. the intermediate compound III according to claim 1, characterized in that the preparation process comprises the following steps: under the protection of inert gas, adding a compound I, namely 2,2, 5-trimethyl-1, 3-dioxane-5-carboxylic acid into an organic solvent for dissolving, cooling, adding an organic base, adding a compound II, namely trimethylsilyl trifluoromethanesulfonate, and stirring at room temperature for reacting to obtain a temsirolimus side chain compound III, wherein the reaction route is as follows:
3. the method according to claim 2, wherein the organic base is one or a combination of triethylamine, pyridine, 2, 6-lutidine, N-diisopropylethylamine.
4. The method according to claim 2, wherein the compound I, the compound II and the organic base are fed in a molar ratio of 1:1.0 to 1.5:1.2 to 2.5.
5. The preparation method according to claim 2, wherein the organic solvent is one or a combination of dichloromethane, N-dimethylformamide, acetonitrile, chloroform and tetrahydrofuran; the temperature of the added organic base is-10 to 10 ℃.
6. Use of compound III according to claim 1 for the preparation of temsirolimus.
7. A process for preparing an important intermediate 2,2, 5-trimethyl-1, 3-dioxane-5-carboxylic acid sirolimus 31-O-trimethylsilylether-42-ester of temsirolimus from the compound III of claim 1, comprising the steps of: dissolving mono-protected sirolimus, namely a compound IV and organic base in an organic solution, adding a side chain compound III at controlled temperature, and reacting at room temperature to obtain an intermediate compound V, wherein the synthetic route is as follows:
8. the preparation method according to claim 7, wherein the organic base is selected from one or a combination of N, N-diisopropylethylamine, triethylamine, pyridine, 4-dimethylaminopyridine and N-methylmorpholine.
9. The method according to claim 7, wherein the organic solvent is selected from one of dichloromethane, N-dimethylformamide, chloroform, tetrahydrofuran, and toluene, or a combination thereof.
10. The preparation method according to claim 7, wherein the feeding molar ratio of the compound IV, the organic base and the compound III is as follows: 1: 4.0-7.0: 2.0-4.0.
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Non-Patent Citations (2)
| Title |
|---|
| DRABOWICZ, J 等: "Product class 1: alkanesulfonic acids and acyclic derivatives", SCIENCE OF SYNTHESIS, vol. 39, pages 17 - 122, XP008143984 * |
| 白文钦等: "坦西莫司的合成工艺优化", 中国医药工业杂志, vol. 49, no. 8, pages 1095 - 1099 * |
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