CN114057792A - Temsirolimus intermediate compound - Google Patents
Temsirolimus intermediate compound Download PDFInfo
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- CN114057792A CN114057792A CN202010743121.0A CN202010743121A CN114057792A CN 114057792 A CN114057792 A CN 114057792A CN 202010743121 A CN202010743121 A CN 202010743121A CN 114057792 A CN114057792 A CN 114057792A
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- temsirolimus
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- intermediate compound
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 62
- 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 30
- 229960000235 temsirolimus Drugs 0.000 title claims abstract description 30
- 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 30
- 238000006243 chemical reaction Methods 0.000 claims abstract description 27
- 238000000034 method Methods 0.000 claims abstract description 19
- 238000001035 drying Methods 0.000 claims abstract description 18
- FCSKOFQQCWLGMV-UHFFFAOYSA-N 5-{5-[2-chloro-4-(4,5-dihydro-1,3-oxazol-2-yl)phenoxy]pentyl}-3-methylisoxazole Chemical compound O1N=C(C)C=C1CCCCCOC1=CC=C(C=2OCCN=2)C=C1Cl FCSKOFQQCWLGMV-UHFFFAOYSA-N 0.000 claims abstract description 17
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims abstract description 16
- 150000007530 organic bases Chemical class 0.000 claims abstract description 14
- 238000010790 dilution Methods 0.000 claims abstract description 12
- 239000012895 dilution Substances 0.000 claims abstract description 12
- 239000003960 organic solvent Substances 0.000 claims abstract description 10
- 238000002360 preparation method Methods 0.000 claims abstract description 7
- 239000002904 solvent Substances 0.000 claims abstract description 5
- 238000001514 detection method Methods 0.000 claims abstract description 4
- 239000011261 inert gas Substances 0.000 claims abstract description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 36
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 27
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 22
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 18
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 17
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 15
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical group CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 12
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 claims description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 12
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 11
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 claims description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 6
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 4
- XWKFPIODWVPXLX-UHFFFAOYSA-N 2-methyl-5-methylpyridine Natural products CC1=CC=C(C)N=C1 XWKFPIODWVPXLX-UHFFFAOYSA-N 0.000 claims 1
- 238000009776 industrial production Methods 0.000 abstract description 4
- 239000006227 byproduct Substances 0.000 abstract description 3
- 239000012535 impurity Substances 0.000 abstract description 3
- 239000000126 substance Substances 0.000 abstract description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 20
- 238000004809 thin layer chromatography Methods 0.000 description 16
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 12
- 229910052757 nitrogen Inorganic materials 0.000 description 10
- 229960001701 chloroform Drugs 0.000 description 9
- 238000003756 stirring Methods 0.000 description 9
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 description 8
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 8
- 238000003786 synthesis reaction Methods 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 5
- 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 description 4
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- QFJCIRLUMZQUOT-HPLJOQBZSA-N sirolimus Chemical class 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 description 4
- 238000000967 suction filtration Methods 0.000 description 4
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 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 description 3
- 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 description 3
- 229960002930 sirolimus Drugs 0.000 description 3
- 239000012312 sodium hydride Substances 0.000 description 3
- 229910000104 sodium hydride Inorganic materials 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 208000008839 Kidney Neoplasms Diseases 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 206010038389 Renal cancer Diseases 0.000 description 1
- 208000006265 Renal cell carcinoma Diseases 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-N Sulfurous acid Chemical compound OS(O)=O LSNNMFCWUKXFEE-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 238000004140 cleaning Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 1
- 201000010982 kidney cancer Diseases 0.000 description 1
- 229940124302 mTOR inhibitor Drugs 0.000 description 1
- 239000003628 mammalian target of rapamycin inhibitor Substances 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- -1 temsirolimus Chemical class 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- 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 System
- 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
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: under the protection of inert gas, adding a compound VI and a compound VII into an organic solvent A, adding organic base, carrying out temperature-controlled reaction, carrying out TLC detection, after the reaction is finished, adding a solvent B for dilution, drying by anhydrous sodium sulfate, and carrying out reduced pressure concentration to obtain a compound I. Provides a novel temsirolimus intermediate compound I; the compound is used for preparing temsirolimus, so that the generation of byproducts can be effectively avoided, new impurities cannot be generated in a synthesized intermediate, the reaction is quicker, economic and environment-friendly, the yield is higher, and the method is suitable for industrial production.
Description
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, is developed by hui pharmaceutical company of usa under the chemical name of sirolimus 42- [ 3-hydroxy-2- (hydroxymethyl) -2-methylpropionate ], is the first application product for treating cancers in mTOR inhibitor drugs, is approved by FDA for treatment of advanced renal cell carcinoma in 5 months of 2007, and is the only drug which can significantly prolong the survival of renal cancer patients at present. Temsirolimus has the following structural formula:
the method comprises the following steps: the synthesis of temsirolimus was first reported in US5362718, the route is as follows:
the synthetic method has the defects that the reaction is not carried out with regioselectivity, rapamycin 28-hydroxyl and rapamycin 40-hydroxyl are easy to esterify when synthesizing temsirolimus, and the separation and purification difficulty of products is large.
The second method comprises the following steps: the synthetic route reported in US2005234086 for temsirolimus is as follows:
although the yield of the method is higher than that of the method, the method has the regioselectivity of 31-position active hydroxyl and 42-position active hydroxyl, impurities and byproducts can be produced, and the production cost is greatly increased 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 operation, short production period, higher yield and is more suitable for industrial production.
The invention content is as follows:
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 using the intermediate.
The specific technical scheme of the invention is as follows:
a temsirolimus intermediate compound is shown in a formula I, and has the following structural formula:
a preparation method of temsirolimus intermediate compound I shown as a formula I comprises the following steps:
the method specifically comprises the following steps:
under the protection of inert gas, adding a compound VI and a compound VII into an organic solvent A, adding organic base, carrying out temperature-controlled reaction, carrying out TLC detection, after the reaction is finished, adding a solvent B for dilution, drying by anhydrous sodium sulfate, and carrying out reduced pressure concentration to obtain a compound I.
Preferably, the organic base is selected from one of N, N-diisopropylethylamine, triethylamine, 2, 6-dimethylpyridine, 4-dimethylaminopyridine and N-methylmorpholine or a combination thereof, and is preferably 4-dimethylaminopyridine.
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 feeding molar ratio of the compound VII to the organic base is 1: 3.0-6.0, wherein 1:4.0 is preferred.
Preferably, the feeding molar ratio of the compound VII to the compound VI is 1: 1.0-2.0, and 1:1.2 is preferred.
Preferably, the solvent B is one of dichloromethane, trichloromethane and ethyl acetate or a combination thereof.
Preferably, the temperature is 0-10 ℃.
The use of the intermediate compound I for preparing temsirolimus.
Wherein compound VI is prepared as follows:
dissolving a compound IV and organic base in an organic solution C, adding a compound V, controlling the temperature, detecting by TLC (thin layer chromatography), drying anhydrous sodium sulfate after the reaction is finished, filtering, and concentrating under reduced pressure to obtain a compound VI, 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 C is selected from one or a combination of dichloromethane, N-dimethylformamide, chloroform, tetrahydrofuran and toluene, wherein dichloromethane is preferred.
Preferably, the charging molar ratio of the compound V to the organic base is 1: 1.0-4.0, and preferably 1: 2.0.
Preferably, the charging molar ratio of the compound V to the compound IV is 1: 1-1.3, and preferably 1: 1.1.
Preferably, the adding temperature is 25-40 ℃, and preferably 30 ℃.
Wherein compound IV is prepared as follows:
under the protection of inert gas, adding a compound III and a compound II into an organic solvent D, controlling the temperature, adding organic base, reacting at room temperature after the addition is finished, detecting by TLC (thin layer chromatography), after the reaction is finished, performing suction filtration, adjusting the pH value to 6-7 by using 0.2M sulfuric acid, extracting by using ethyl acetate, combining organic phases, drying by using anhydrous sodium sulfate, filtering, and performing reduced pressure concentration to obtain a 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, lithium diisopropylamide, and sodium hydride is preferred.
Preferably, the feeding molar ratio of the compound II to the compound III is 1: 1.0-1.5, and preferably 1: 1.2.
Preferably, the feeding molar ratio of the compound II to the organic base is 1: 2-2.5, and preferably 1: 2.2.
Preferably, the organic solvent D is one of dichloromethane, 1, 4-dioxane, acetonitrile, chloroform, tetrahydrofuran, or a combination thereof, and preferably tetrahydrofuran.
Preferably, the temperature of the added organic base is-5 ℃, and particularly preferably 0 ℃.
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, carrying out temperature-controlled reaction, carrying out TLC detection, washing the saturated sodium bicarbonate solution and the saturated saline solution for three times after the reaction is finished, combining organic phases, drying, carrying out suction filtration, and carrying out reduced pressure concentration 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 3 mol/L.
Preferably, the organic solvent E is selected from one or a combination of dichloromethane, N-dimethylformamide, chloroform, tetrahydrofuran and toluene, with tetrahydrofuran being particularly preferred.
Preferably, the feeding ratio of the compound I to the acid is as follows: 1: 1.0-4.0, particularly preferably 1:2.0, g/mL.
Preferably, the temperature is 0-10 ℃, and preferably 5 ℃.
The invention has the technical effects that:
the invention provides a novel temsirolimus intermediate compound I; the compound is used for preparing temsirolimus, so that the generation of byproducts can be effectively avoided, new impurities cannot be generated in a synthesized intermediate, the reaction is quicker, 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, which should be properly understood: the examples of the present invention are merely illustrative and not restrictive, and therefore, the present invention may be modified in a simple manner without departing from the scope of the invention as claimed.
In the following examples, various procedures and methods not described in detail are conventional methods well known in the art.
The structure of the temsirolimus intermediate compound I is confirmed as follows:
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 a compound III (28.14g,0.21mol) and a compound II (84.00g,0.2mol) into 45ml of tetrahydrofuran, controlling the temperature to be 0 ℃, adding sodium hydride (16.80g,0.42mol), raising the temperature to room temperature for reaction after the addition is finished, detecting by TLC (thin layer chromatography), after the reaction is finished, performing suction filtration, adjusting the pH to be 6-7 by using 0.2M sulfuric acid, extracting by using ethyl acetate, combining organic phases, drying by using anhydrous sodium sulfate, filtering, and concentrating under reduced pressure to obtain a compound IV, wherein the yield is 97.5%, and the purity is 99.72%.
Example 2
Synthesis of Compound VI:
dissolving compound IV (41.41g, 0.21mol) and N, N-diisopropylethylamine (51.7g,0.4mol) in 250ml of EDCM, adding compound V (48.76g,0.20mol), controlling the temperature at 30 ℃, detecting by TLC, after the reaction is finished, washing with purified water for 3 times, drying with anhydrous sodium sulfate, filtering, and concentrating under reduced pressure to obtain compound VI with the yield of 99.83% and the purity of 99.76%.
Example 3
Synthesis of Compound I:
under the protection of nitrogen, adding a compound VII (91.34g, 0.1mol) and a compound VI (72.22g, 0.12mol) into 500mL of dichloromethane, stirring and dissolving, adding 4-dimethylaminopyridine (48.86g, 0.40mol), controlling the temperature after dissolution to be 5 ℃, detecting by TLC (thin layer chromatography), adding ethyl acetate for dilution after the reaction is finished, drying by anhydrous sodium sulfate, and concentrating under reduced pressure to obtain a compound I, wherein the yield is 98.2% and the purity is 99.92%.
Example 4
Under the protection of nitrogen, adding a compound VII (45.67g, 0.05mol) and a compound VI (60.20g, 0.10mol) into 500mLN, N-dimethylformamide, stirring and dissolving, adding N, N-diisopropylethylamine (51.7g, 0.40mol), controlling the temperature to be 0 ℃ after dissolving and cleaning, detecting by TLC, after the reaction is finished, adding dichloromethane for dilution, drying by anhydrous sodium sulfate, and concentrating under reduced pressure to obtain a compound I, wherein the yield is 95.5%, and the purity is 99.89%.
Example 5
Under the protection of nitrogen, adding a compound VII (45.67g, 0.05mol) and a compound VI (120.36g, 0.20mol) into 600mL of trichloromethane, stirring and dissolving, adding triethylamine (202.38g, 0.40mol), controlling the temperature to 10 ℃ after dissolving, detecting by TLC, adding trichloromethane for dilution after the reaction is finished, drying by anhydrous sodium sulfate, and concentrating under reduced pressure to obtain a compound I, wherein the yield is 95.4%, and the purity is 99.82%.
Example 6
Under the protection of nitrogen, adding a compound VII (91.34g, 0.10mol) and a compound VI (48.14g, 0.08mol) into 550mL tetrahydrofuran, stirring and dissolving, adding 2, 6-dimethylpyridine (42.86g, 0.40mol), controlling the temperature after dissolving and clearing at 5 ℃, detecting by TLC (thin layer chromatography), adding ethyl acetate for dilution after the reaction is finished, drying by anhydrous sodium sulfate, and concentrating under reduced pressure to obtain a compound I, wherein the yield is 93.2% and the purity is 99.78%.
Example 7
Under the protection of nitrogen, adding a compound VII (91.34g, 0.10mol) and a compound VI (144.44g, 0.24mol) into 500mL of toluene, stirring and dissolving, adding N-methylmorpholine (40.46g, 0.40mol), controlling the temperature after dissolving to be 8 ℃, detecting by TLC, adding ethyl acetate for dilution after the reaction is finished, drying by anhydrous sodium sulfate, and concentrating under reduced pressure to obtain a compound I, wherein the yield is 92.6 percent, and the purity is 99.74 percent.
Example 8
Under the protection of nitrogen, adding a compound VII (91.34g, 0.10mol) and a compound VI (72.22g, 0.12mol) into 600mL of dioxane, stirring for dissolving, adding 4-dimethylaminopyridine (36.64g, 0.30mol), controlling the temperature to be 5 ℃ after dissolving, detecting by TLC (thin layer chromatography), after the reaction is finished, adding trichloromethane for dilution, drying by anhydrous sodium sulfate, and concentrating under reduced pressure to obtain a compound I, wherein the yield is 96.6%, and the purity is 99.83%.
Example 9
Under the protection of nitrogen, adding a compound VII (91.34g, 0.10mol) and a compound VI (72.22g, 0.12mol) into 500mLN, N-dimethylformamide, stirring and dissolving, adding 4-dimethylaminopyridine (73.3g, 0.60mol), controlling the temperature to be 5 ℃ after dissolving, detecting by TLC (thin layer chromatography), after the reaction is finished, adding ethyl acetate for dilution, drying by anhydrous sodium sulfate, and concentrating under reduced pressure to obtain a compound I, wherein the yield is 96.5% and the purity is 99.81%.
Example 10
Under the protection of nitrogen, adding a compound VII (91.34g, 0.10mol) and a compound VI (72.22g, 0.12mol) into 550mL of trichloromethane, stirring and dissolving, adding 4-dimethylaminopyridine (24.42g, 0.20mol), controlling the temperature to be 10 ℃ after dissolving, detecting by TLC (thin layer chromatography), adding ethyl acetate for dilution after the reaction is finished, drying by anhydrous sodium sulfate, and concentrating under reduced pressure to obtain a compound I, wherein the yield is 96.0% and the purity is 99.82%.
Example 11
Under the protection of nitrogen, adding a compound VII (91.34g, 0.10mol) and a compound VI (72.22g, 0.12mol) into 600mL tetrahydrofuran, stirring and dissolving, adding 4-dimethylamino pyridine (85.5g, 0.70mol), controlling the temperature to be 5 ℃ after dissolving, detecting by TLC (thin layer chromatography), adding dichloromethane for dilution after the reaction is finished, drying by anhydrous sodium sulfate, and concentrating under reduced pressure to obtain a compound I, wherein the yield is 96.2% and the purity is 99.76%.
Example 12
Adding a compound I (12.90g, 0.01mol) into tetrahydrofuran, slowly adding 3mol/L sulfuric acid (26mL), controlling the temperature to 5 ℃ for reaction, detecting by TLC, washing three times by using a saturated sodium bicarbonate solution and a saturated saline solution after the reaction is finished, combining organic phases, drying, carrying out suction filtration, and carrying out reduced pressure concentration to obtain a target compound, namely temsirolimus, wherein the yield is 94.2%, and the purity is 99.80%.
Claims (10)
1. A temsirolimus intermediate compound is shown in a formula I, and has the following structural formula:
2. a process for the preparation of temsirolimus intermediate compound I of claim 1, wherein compound VI is reacted with compound VII to give intermediate compound I, according to the following formula:
3. the method for preparing temsirolimus intermediate compound I according to claim 2, comprising the following steps: under the protection of inert gas, adding a compound VI and a compound VII into an organic solvent A, adding organic base, carrying out temperature-controlled reaction, carrying out TLC detection, after the reaction is finished, adding a solvent B for dilution, drying by anhydrous sodium sulfate, and carrying out reduced pressure concentration to obtain a compound I.
4. The method according to claim 3, wherein the organic base is selected from N, N-diisopropylethylamine, triethylamine, 2, 6-lutidine, 4-dimethylaminopyridine, N-methylmorpholine, or a combination thereof.
5. The preparation method according to claim 3, wherein the organic solvent A is selected from one or a combination of dichloromethane, N-dimethylformamide, chloroform, tetrahydrofuran, toluene and dioxane.
6. The preparation method according to claim 3, wherein the molar ratio of the compound VII and the organic base is 1:3.0 to 6.0.
7. The method according to claim 3, wherein the molar ratio of the compound VII to the compound VI is 1:1.0 to 2.0.
8. The method according to claim 3, wherein the solvent B is one of dichloromethane, chloroform and ethyl acetate or a combination thereof.
9. The method according to claim 3, wherein the temperature is 0 to 10 ℃.
10. Use of the intermediate compound I of claim 1 for the preparation of temsirolimus.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107561170A (en) * | 2016-07-02 | 2018-01-09 | 山东新时代药业有限公司 | A kind of analyzing detecting method of CCI-779 intermediate |
| 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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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107561170A (en) * | 2016-07-02 | 2018-01-09 | 山东新时代药业有限公司 | A kind of analyzing detecting method of CCI-779 intermediate |
| 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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