CN114057793A - Tacrolimus derivative - Google Patents
Tacrolimus derivative Download PDFInfo
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- CN114057793A CN114057793A CN202010744034.7A CN202010744034A CN114057793A CN 114057793 A CN114057793 A CN 114057793A CN 202010744034 A CN202010744034 A CN 202010744034A CN 114057793 A CN114057793 A CN 114057793A
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- QJJXYPPXXYFBGM-LFZNUXCKSA-N Tacrolimus Chemical class C1C[C@@H](O)[C@H](OC)C[C@@H]1\C=C(/C)[C@@H]1[C@H](C)[C@@H](O)CC(=O)[C@H](CC=C)/C=C(C)/C[C@H](C)C[C@H](OC)[C@H]([C@H](C[C@H]2C)OC)O[C@@]2(O)C(=O)C(=O)N2CCCC[C@H]2C(=O)O1 QJJXYPPXXYFBGM-LFZNUXCKSA-N 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 69
- 238000006243 chemical reaction Methods 0.000 claims abstract description 49
- 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 14
- 150000007530 organic bases Chemical class 0.000 claims abstract description 14
- 238000002360 preparation method Methods 0.000 claims abstract description 14
- CBPNZQVSJQDFBE-FUXHJELOSA-N Temsirolimus Chemical class 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 claims abstract description 12
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims abstract description 9
- 238000001035 drying Methods 0.000 claims abstract description 9
- 238000001514 detection method Methods 0.000 claims abstract description 8
- 238000010790 dilution Methods 0.000 claims abstract description 8
- 239000012895 dilution Substances 0.000 claims abstract description 8
- 239000003960 organic solvent Substances 0.000 claims abstract description 8
- 239000011261 inert gas Substances 0.000 claims abstract description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 45
- 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 29
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 22
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-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
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 12
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-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
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 claims description 9
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-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 7
- 238000000034 method Methods 0.000 claims description 5
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 4
- 150000001335 aliphatic alkanes Chemical class 0.000 claims description 4
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 4
- 239000002904 solvent Substances 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 description 2
- 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 abstract description 10
- 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 abstract description 9
- 229960002930 sirolimus Drugs 0.000 abstract description 9
- 230000009286 beneficial effect Effects 0.000 abstract description 2
- 238000005886 esterification reaction Methods 0.000 abstract description 2
- 239000000243 solution Substances 0.000 abstract description 2
- 239000000126 substance Substances 0.000 abstract description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 48
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 24
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 24
- 238000004809 thin layer chromatography Methods 0.000 description 21
- 230000015572 biosynthetic process Effects 0.000 description 20
- 238000003786 synthesis reaction Methods 0.000 description 20
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 18
- 238000005160 1H NMR spectroscopy Methods 0.000 description 18
- 229910052757 nitrogen Inorganic materials 0.000 description 12
- 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 9
- 229960001701 chloroform Drugs 0.000 description 9
- 238000001914 filtration Methods 0.000 description 9
- 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 8
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 8
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 5
- 239000012312 sodium hydride Substances 0.000 description 5
- 229910000104 sodium hydride Inorganic materials 0.000 description 5
- 238000000967 suction filtration Methods 0.000 description 5
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 4
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 230000000259 anti-tumor effect Effects 0.000 description 2
- 238000004140 cleaning Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 229960000235 temsirolimus Drugs 0.000 description 2
- 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 description 2
- 239000002841 Lewis acid Substances 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 208000006265 Renal cell carcinoma Diseases 0.000 description 1
- 102000013530 TOR Serine-Threonine Kinases Human genes 0.000 description 1
- 108010065917 TOR Serine-Threonine Kinases Proteins 0.000 description 1
- 102000018679 Tacrolimus Binding Proteins Human genes 0.000 description 1
- 108010027179 Tacrolimus Binding Proteins Proteins 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 150000001336 alkenes Chemical class 0.000 description 1
- 125000003342 alkenyl group Chemical group 0.000 description 1
- 125000003368 amide group Chemical group 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 230000032823 cell division Effects 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- 150000007517 lewis acids Chemical class 0.000 description 1
- 150000002678 macrocyclic compounds Chemical class 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 150000004291 polyenes Chemical class 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 230000003334 potential effect Effects 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 238000007142 ring opening reaction Methods 0.000 description 1
- 238000005556 structure-activity relationship Methods 0.000 description 1
- 125000000542 sulfonic acid group Chemical group 0.000 description 1
- NQRYJNQNLNOLGT-UHFFFAOYSA-N tetrahydropyridine hydrochloride Natural products C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 1
- 238000006257 total synthesis reaction Methods 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 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
- C07F9/6574—Esters of oxyacids of phosphorus
- C07F9/65742—Esters of oxyacids of phosphorus non-condensed with carbocyclic rings or heterocyclic rings or ring systems
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Abstract
The invention belongs to the field of pharmaceutical chemicals, and particularly relates to a temsirolimus derivative; the preparation method of the temsirolimus derivative comprises the steps of inert gas protection, adding a compound VI and a compound VII into an organic solvent, adding an organic base, carrying out temperature-controlled reaction, carrying out TLC detection, after the reaction is finished, adding a solution for dilution, drying with anhydrous sodium sulfate, and carrying out reduced pressure concentration to obtain a compound I; provides a new intermediate compound VI, which can effectively improve the regioselectivity of rapamycin esterification reaction, is beneficial to the reaction of 42-hydroxyl and can effectively avoid the reaction of 31-hydroxyl.
Description
Technical Field
The invention belongs to the field of pharmaceutical chemicals, and particularly relates to a temsirolimus derivative.
Background
Temsirolimus (Temsirolimus, trade name:) Was developed by Prohewski pharmaceutical company and approved by the U.S. FDA for marketing at 5 months 2007 for the treatment of renal cell carcinoma. The action mechanism is similar to that of rapamycin, and the rapamycin and FKBP and mTOR are combined to form a complex, so that cell division is inhibited. This suggests that rapamycin and its analogues have potential activity against tumors, and based on this mechanism rapamycin was later used in antitumor studies to obtain a series of derivatives and test their antitumor activity.
Rapamycin is structurally complex, has 31 atoms in the formed macrocycle, has 15 chiral centers, and all alkenyl groups are all-trans structures, and due to these factors, it is difficult to perform total synthesis or synthesis efficiency is too low, not suitable for industrial production, and not economical and environmentally friendly. The method employed in the synthesis of rapamycin analogues is therefore semi-synthetic. Mainly comprises modifying hydroxyl, polyene and piperidine ester group, or enlarging large ring by ring-expanding reaction. Rappa by researchersTri-alkenyl of the mycin with Lewis acid (SnCl)4,BF3–OEt2Etc. as catalysts), but in these reactions, the sites of reaction are not specific, resulting in a mixture of multiple alkenes and alkanes.
In addition, rapamycin undergoes a ring-opening reaction after being metabolized by a human body, oxygen at the 24-position is hydrolyzed with a carbonyl group connected with the rapamycin, and secorapamycins are generated. .
As can be seen from the structure-activity relationship, modification of the hydroxyl group at position 42 can change the properties of the compound and increase the activity of the drug. In general, the reactivity is generally good after the reaction with the hydroxyl group at position 42 to form an ester group, a sulfonic acid group, or an amide group. Since there is also a hydroxyl group at position 31, the hydroxyl group at position 31 must also react during the reaction to obtain a mixture of the two, which can only be separated by chromatography, and there is no specific reaction at position 42.
In view of the above problems, the present invention provides a temsirolimus derivative which is advantageous for the reaction of the hydroxyl group at the 42-position and can effectively avoid the reaction of the hydroxyl group at the 31-position, and the compound obtained by the preparation method is non-toxic, highly selective and suitable for industrial production.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provide a temsirolimus derivative.
The specific technical scheme of the invention is as follows:
a temsirolimus derivative is shown as a formula I, and has the following structural formula:
a preparation method of temsirolimus derivative shown as a formula I comprises the following steps:
wherein R is1is-H, -OH, -C1-C4 alkane, -OCH3,-COCH3,-COCH2CH3,-OCH2COCH3; n=0,1,2,3,4。
R1preferably-H, propyl, -OH; n is 0, 3.
R1Further preferably a propyl group; n is 3.
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 or a combination of N, N-diisopropylethylamine, triethylamine, 2, 6-dimethyl pyridine, 4-dimethylamino pyridine and N-methyl morpholine, and further preferably is 4-dimethylamino pyridine.
Preferably, the organic solvent a is selected from one or a combination of dichloromethane, N-dimethylformamide, chloroform, tetrahydrofuran, toluene and dioxane, and further preferably dichloromethane.
Preferably, the feeding molar ratio of the compound VII and the organic base is 1: 3.0-6.0, and more preferably 1: 4.0.
Preferably, the feeding molar ratio of the compound VII to the compound VI is 1: 1.0-2.0, and more preferably 1: 1.2.
Preferably, the solvent B is one of dichloromethane, trichloromethane and ethyl acetate or a combination thereof.
Preferably, the temperature-controlled reaction temperature is 0-10 ℃, and more preferably 5 ℃.
Preparation of Compound IV
The reaction route is as follows:
wherein R is1is-H, -OH, -C1-C4 alkane, -OCH3,-COCH3,-COCH2CH3,-OCH2COCH3; n=0,1,2,3,4。
R1preferably-H, propyl, -OH; n is 0, 3.
R1Further preferably a propyl group; n is 3.
The preparation method comprises the following steps:
and (3) under the protection of inert gas, adding the compound III and the compound II into an organic solvent C, adding an organic base at a controlled temperature, reacting at room temperature after the addition is finished, detecting by TLC, filtering after the reaction is finished, and concentrating under reduced pressure to obtain a compound IV.
Preferably, the organic base is selected from one or a combination of sodium hydride, sodium methoxide, potassium tert-butoxide, n-butyllithium, lithium diisopropylamide, and particularly preferably sodium hydride.
Preferably, the feeding molar ratio of the compound II to the compound III is 1:1.0 to 1.5, particularly preferably 1: 1.2.
Preferably, the feeding molar ratio of the compound II to the organic base is 1:2 to 2.5, particularly preferably 1: 2.2.
preferably, the organic solvent C is one or a combination of dichloromethane, 1, 4-dioxane, acetonitrile, chloroform and tetrahydrofuran, and particularly preferably tetrahydrofuran.
Preferably, the temperature of the added organic base is-5 ℃, and particularly preferably 0 ℃.
Preparation of Compound VI
The reaction route is as follows:
wherein R is1is-H, -OH, -C1-C4 alkaneHydrocarbon, -OCH3,-COCH3,-COCH2CH3,-OCH2COCH3; n=0,1,2,3,4。
R1preferably-H, propyl, -OH; n is 0, 3.
R1Further preferably a propyl group; n is 3.
The preparation method comprises the following steps:
dissolving the compound IV and organic base in the organic solution D, adding the compound V, controlling the temperature, detecting by TLC, filtering after the reaction is finished, and concentrating under reduced pressure to obtain a compound VI.
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 D is selected from one or a combination of dichloromethane, N-dimethylformamide, chloroform, tetrahydrofuran and toluene, and more preferably dichloromethane.
Preferably, the charging molar ratio of the compound V to the organic base is 1: 1.0-4.0, and more preferably 1: 2.0.
Preferably, the charging molar ratio of the compound V to the compound IV is 1: 1.0-1.3.0, and more preferably 1: 1.1.
Preferably, the adding temperature is 25-40 ℃, and more preferably 30 ℃.
Compared with the prior art, the invention has the following technical effects:
1. a temsirolimus derivative is provided;
2. the new intermediate compound VI provided by the invention can effectively improve the regioselectivity of rapamycin esterification reaction due to large steric hindrance in the reaction process, is beneficial to the reaction of 42-hydroxyl, and can effectively avoid the reaction of 31-hydroxyl.
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:
when R1 is H, n is 0,
example 1
Synthesis of compound IV:
under the protection of nitrogen, adding a compound II (16.62g, 0.1mol) and a compound III (16.10g, 0.12mol) into 30ml of tetrahydrofuran, controlling the temperature to be 0 ℃, adding sodium methoxide (11.88g, 0.22mol), raising the temperature to room temperature for reaction after the addition is finished, detecting by TLC, after the reaction is finished, carrying out suction filtration, and concentrating under reduced pressure to obtain a compound IV, wherein the yield is 97.5%, and the purity is 99.76%.
Synthesis of Compound VI:
compound IV (29.50g, 0.1mol) and N, N-diisopropylethylamine (25.85g, 0.2mol) were dissolved in 120mL of dichloromethane, and Compound V (24.39g,0.10mol) was added thereto, the temperature was controlled at 35 ℃ and TLC detection was performed, after the reaction was completed, filtration and concentration under reduced pressure were carried out to give Compound VI in 96.1% yield and 99.70% purity.
Synthesis of Compound I:
under the protection of nitrogen, adding a compound VII (45.74g, 0.05mol) and a compound VI (27.46g, 0.06mol) into 300mL of toluene, stirring and dissolving, adding 4-dimethylaminopyridine (24.44g, 0.20mol), controlling the temperature to be 0 ℃ 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 95.5% and the purity is 99.89%.
Compound IV:
1H-NMR(400MHz,CDCl3)δ:1.31(s,3H),3.54~3,62(m,2H),3.69~3.91(m,6H), 3.97~4.06(m,2H),4.23~4.47(m,2H),11.94(s,1H);
13CNMR(100MHz,CDCl3)δ:15.9,45.8,60.3,60.3,71.9,71.9,73.1,73.1,179.5
ESI-HRMS:m/z=269.2031[M+H]+;
compound VI:
1H-NMR(400MHz,CDCl3)δ:1.27(s,3H),3.44~3,50(m,2H),3.64~3.88(m,6H), 3.92~4.01(m,2H),4.20~4.37(m,2H),7.73(s,2H);
13CNMR(100MHz,CDCl3)δ:15.4,43.8,60.6,60.6,71.1,71.1,72.2,72.2,127.9,127.9,132.7,138.3,183.3,143.5,151.9,178.5
ESI-HRMS:m/z=475.1313[M+H]+;
a compound I:
1H-NMR(400MHz,DMSO-d6)δ:0.73(d,J=6.6Hz,3H),0.78(d,J=6.0Hz,3H),0.80 (d,J=6.0Hz,3H),0.85(d,J=6.0Hz,3H),0.97(d,J=6.6Hz,3H),1.10(s,3H),1.11~1.18 (m,2H),1.44(s,3H),1.52~1.59(m,6H),1.66(s,3H),1.75(s,3H),1.79(s,3H), 1.92~2.01(m,3H),2.14~2.21(m,2H),2.20~2.24(t,J=4.6Hz,2H),2.36~2.74(m,3H), 3.12(s,3H),3.17(s,3H),3.15~3.31(m,5H),3.39~3.51(m,6H),3.60(d,J=11.4Hz,1H), 3.65(dd,J=12.4、10.2Hz,2H),3.73~3.77(m,4H),3.80~3.84(m,4H),3.96(d,J=3.6Hz,1H), 4.05~4.13(m,1H),4.17(dd,J=12.4、10.2Hz,2H),4.24(br s,1H),4.36~4.48(m,1H), 4.56(t,J=4.5Hz,2H),4.58~4.63(m,4H),4.93(d,J=3.6Hz,1H),4.97~5.09(m,1H), 5.13(d,J=10.2Hz,1H),5.32(d,J=4.2Hz,1H),5.44(dd,J=14.4、10.2Hz,1H),6.11~6.16 (m,2H),6.23(t,J=10.2Hz,1H),6.37(dd,J=13.8、11.4Hz,1H),6.62(s,1H);
13CNMR(100MHz,DMSO-d6)δ:10.6,12.9,14.2,15.0,15.6,16.7,17.3,20.8, 22.5,24.6,25.7,26.3,27.1,29.6,30.2,31.1,33.4,33.8,35.5,35.6,36.5,38.8, 39.6,40.1,40.3,40.5,45.0,45.4,50.3,51.1,56.6,57.9,58.1,60.6,60.6,64.2, 64.2,66.8,72.4,72.5,73.3,73.3,74.2,76.6,76.6,80.9,82.2,85.6,99.7,125.3, 127.7,131.1,132.8,137.4,138.0,139.6,167.1,169.6,174.6,175.8,199.4,208.2, 211.3.
ESI-HRMS:m/z=1178.6352[M+H]+;
when R1 is H and n is 3
Example 2
Synthesis of compound IV:
under the protection of nitrogen, adding a compound II (25.03g, 0.10mol) and a compound III (20.13g, 0.15mol) into 30ml of acetonitrile, controlling the temperature to be 2 ℃, adding sodium hydride (24.69g, 0.22mol), raising the temperature to room temperature for reaction after the addition is finished, detecting by TLC, after the reaction is finished, carrying out suction filtration, and carrying out reduced pressure concentration to obtain a compound IV, wherein the yield is 97.0%, and the purity is 99.71%.
Synthesis of Compound VI:
dissolving the compound IV (35.24g, 0.10mol) and N, N-diisopropylethylamine (25.85g, 0.2mol) in 120mL of N, N-dimethylformamide, adding the compound V (24.39g,0.10mol), controlling the temperature at 25 ℃, detecting by TLC, after the reaction is finished, filtering, and concentrating under reduced pressure to obtain the compound VI, wherein the yield is 96.4%, and the purity is 99.67%.
Synthesis of Compound I:
under the protection of nitrogen, adding a compound VII (45.74g, 0.05mol) and a compound VI (33.59g, 0.06mol) into 300mLN, N-dimethylformamide, stirring and dissolving, adding N, N-diisopropylethylamine (25.85g, 0.20mol), controlling the temperature to be 10 ℃ after dissolving and cleaning, detecting by TLC (thin layer chromatography), 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 95.0% and the purity is 99.84%.
Compound IV:
1H-NMR(400MHz,CDCl3)δ:1.52(s,3H),2.03~2.28(m,12H),3.50~3.63(m,6H), 3.71~4.79(m,4H)3.99~4.14(m,2H),4.25(s,1H),12.06(s,1H);
13CNMR(100MHz,CDCl3)δ:15.4,20.9,20.9,29.6,29.6,31.1,31.1,45.2,57.9, 57.9,72.4,72.4,73.6,73.6,179.2.
ESI-HRMS:m/z=353.1724[M+H]+;
compound VI:
1H-NMR(400MHz,CDCl3)δ:1.53(s,3H),2.01~2.30(m,12H),3.56~3.64(m,6H), 3.69~4.78(m,4H)3.95~4.11(m,2H),5.33(s,1H),7.81(s,2H);
13CNMR(100MHz,CDCl3)δ:15.1,20.5,20.5,29.7,29.7,30.9,30.9,44.4,57.6, 57.6,72.2,72.2,73.4,73.4,127.7,127.7,131,8,138.2,138.2,142.4,153.0,179.2.
ESI-HRMS:m/z=559.0703[M+H]+;
a compound I:
1H-NMR(400MHz,DMSO-d6)δ:0.69(d,J=6.6Hz,3H),0.78(d,J=6.0Hz,3H),0.82 (d,J=6.0Hz,3H),0.88(d,J=6.0Hz,3H),0.97(d,J=6.6Hz,3H),1.15(s,3H),1.09~1.16 (m,2H),1.42(s,3H),1.54~1.59(m,6H),1.69(s,3H),1.76(s,3H),1.80(s,3H), 1.85~1.91(m,4H),1.94~1.99(m,4H),2.04~2.08(m,3H),2.11~216(m,4H),2.20~2.15 (m,4H),2.19~2.23(m,2H),2.27~2.32(t,J=4.6Hz,2H),2.47~2.78(m,3H),3.16(s,3H), 3.21(s,3H),3.28~3.33(m,5H),3.39~3.50(m,6H),3.65(d,J=11.4Hz,1H),3.67~3.70 (m,4H),3.74(dd,J=12.4、10.2Hz,2H),3.94(d,J=3.6Hz,1H),4.03~4.11(m,1H), 4.16(dd,J=12.4、10.2Hz,2H),4.25(br s,1H),4.38~4.49(m,1H),4.54(t,J=4.5Hz,2H), 4.57~4.61(m,4H),4.95(d,J=3.6Hz,1H),4.99~5.11(m,1H),5.14(d,J=10.2Hz,1H), 5.17(s,1H),5.33(d,J=4.2Hz,1H),5.45(dd,J=14.4、10.2Hz,1H),6.12~6.17(m,2H), 6.24(t,J=10.2Hz,1H),6.39(dd,J=13.8、11.4Hz,1H),6.64(s,1H);
13CNMR(100MHz,DMSO-d6)δ:11.3,13.7,14.2,15.5,15.8,16.7,17.5,20.7, 20.8,21.0,22.9,24.9,26.7,27.4,28.6,28.7,29.4,29.5,30.0,30.7,31.4,33.8, 34.1,35.8,35.9,36.7,38.8,39.5,40.1,40.3,40.5,43.8,44.8,45.4,50.7,51.3, 56.4,57.8,58.0,64.2,64.3,66.9,70.5,70.6,73.1,73.2,74.1,75.5,75.6,76.7, 76.7,80.8,82.5,86.0,99.4,125.2,127.8,130.7,132.9,137.4,138.3,139.8,167.1, 169.8,174.5,175.7,199.7,208.2,211.3.
ESI-HRMS:m/z=1248.7115[M+H]+;
when R1 is OH and n is 0
Example 3
Synthesis of compound IV:
under the protection of nitrogen, adding a compound II (18.22g, 0.10mol) and a compound III (17.45g, 0.13mol) into 30ml of anhydrous 1, 4-dioxane, controlling the temperature to be-2 ℃, adding n-butyl lithium (14.09g, 0.22mol), controlling the temperature to be-2 ℃ for reaction after the addition is finished, detecting by TLC, filtering after the reaction is finished, and concentrating under reduced pressure to obtain a compound IV, wherein the yield is 97.1 percent and the purity is 99.72 percent.
Synthesis of Compound VI:
compound IV (28.42g, 0.10mol) and N, N-diisopropylethylamine (25.85g, 0.2mol) were dissolved in 120mL of chloroform, and compound V (24.39g,0.10mol) was added thereto, the temperature was controlled at 40 ℃ and TLC detection was performed, after the reaction was completed, filtration and concentration under reduced pressure were carried out to obtain compound VI in 97.0% yield and 99.70% purity.
Synthesis of Compound I:
under the protection of nitrogen, adding a compound VII (45.74g, 0.05mol) and a compound VI (29.50g, 0.06mol) into 300mL of trichloromethane, stirring and dissolving, adding 2, 6-lutidine (21.43g, 0.20mol), controlling the temperature after dissolving and cleaning to be 5 ℃, detecting by TLC, 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 94.8%, and the purity is 99.80%.
Compound IV:
1H-NMR(400MHz,CDCl3)δ:1.34(s,3H),3.44~3.56(m,2H),3.80~4.04(m,6H), 4.16~4.23(m,2H),4.83~4.97(m,2H),5.34(s,1H),12.21(s,1H);
13CNMR(100MHz,CDCl3)δ:15.6,45.3,68.9,68.9,70.9,70.9,72.1,72.1,179.1
ESI-HRMS:m/z=285.0732[M+H]+;
compound VI:
1H-NMR(400MHz,CDCl3)δ:1.42(s,3H),3.40~3.51(m,2H),3.83~4.08(m,6H),4.14~4.21(m,2H),4.79~4.95(m,2H),5.31(s,1H),7.70(s,2H);
13CNMR(100MHz,CDCl3)δ:15.7,42.9,60.3,60.3,71.6,71.6,72.7,72.7,128.2, 128.2,133.0,138.8,183.8,143.3,151.4,177.9;
ESI-HRMS:m/z=491.1125[M+H]+;
a compound I:
1H-NMR(400MHz,DMSO-d6)δ:0.74(d,J=6.6Hz,3H),0.79(d,J=6.0Hz,3H),0.83 (d,J=6.0Hz,3H),0.88(d,J=6.0Hz,3H),0.98(d,J=6.6Hz,3H),1.09(s,3H),1.12~1.21 (m,2H),1.43(s,3H),1.49~1.59(m,6H),1.67(s,3H),1.75(s,3H),1.79(s,3H), 1.93~2.01(m,3H),2.12~2.18(m,2H),2.22~2.26(t,J=4.6Hz,2H),2.35~2.76(m,3H), 3.09(s,3H),3.17(s,3H),3.16~3.29(m,5H),3.38~3.48(m,6H),3.60(d,J=11.4Hz,1H), 3.67(dd,J=12.4、10.2Hz,2H),3.73~3.82(m,4H),3.95(d,J=3.6Hz,1H),4.04~4.12(m,1H), 4.15(dd,J=12.4、10.2Hz,2H),4.24~4.32(m,4H),4.39(br s,1H),4.42~4.49(m,1H), 4.56(t,J=4.5Hz,2H),4.61~4.71(m,4H),4.94(d,J=3.6Hz,1H),4.96~5.05(m,1H), 5.14(d,J=10.2Hz,1H),5.33(d,J=4.2Hz,1H),5.46(dd,J=14.4、10.2Hz,1H),5.65(S,1H), 6.11~6.16(m,2H),6.25(t,J=10.2Hz,1H),6.39(dd,J=13.8、11.4Hz,1H),6.63(s,1H);
13CNMR(100MHz,DMSO-d6)δ:10.3,12.7,14.0,15.1,15.6,16.7,17.3,20.8, 22.4,24.7,25.7,26.3,27.1,29.6,30.2,31.1,33.4,33.8,35.5,35.6,36.5,38.8, 39.6,40.1,40.3,40.5,45.0,45.4,50.3,51.1,56.6,57.9,58.1,64.2,64.2,60.6, 60.6,66.8,70.4,70.5,73.3,73.3,74.2,76.7,76.7,80.9,82.2,85.6,99.7,125.3, 127.6,131.1,132.8,137.4,138.0,139.6,167.1,169.6,174.6,175.8,199.4,208.1, 211.2.
ESI-HRMS:m/z=1194.6351[M+H]+;
when R1 is OH and n is 3
Example 4
Synthesis of compound IV:
under the protection of nitrogen, adding a compound II (26.63g, 0.10mol) and a compound III (16.11g, 0.12mol) into 30ml of trichloromethane, controlling the temperature to be-5 ℃, adding lithium diisopropylamide (23.57g, 0.22mol), raising the temperature to room temperature for reaction after the addition is finished, detecting by TLC (thin layer chromatography), reducing the temperature to 0 ℃ after the reaction is finished, performing suction filtration, and concentrating under reduced pressure to obtain a compound IV, wherein the yield is 97.4%, and the purity is 99.77%.
Synthesis of Compound VI:
compound IV (40.52g, 0.11mol) and N, N-diisopropylethylamine (38.78g, 0.3mol) were dissolved in 120mL tetrahydrofuran, and Compound V (24.39g,0.10mol) was added thereto, the temperature was controlled at 35 ℃ and TLC detection was performed, after the reaction was completed, filtration and concentration under reduced pressure were carried out to give Compound VI in 97.3% yield with a purity of 99.74%.
Synthesis of Compound I:
under the protection of nitrogen, adding a compound VII (45.74g, 0.05mol) and a compound VI (34.55g, 0.06mol) into 300mL tetrahydrofuran, stirring and dissolving, adding N-methylmorpholine (20.23g, 0.20mol), controlling the temperature to be 0 ℃ 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 95.3%, and the purity is 99.85%.
Compound IV:
1H-NMR(400MHz,CDCl3)δ:1.35(s,3H),2.18~2.45(m,12H),3.59~3.72(m,6H), 4.06~4.12(m,2H),4.55~4.67(m,4H),5.01(s,1H),11.95(s,1H);
13CNMR(100MHz,CDCl3)δ:15.1,19.9,19.9,28.2,28.2,28.7,28.7,45.0,65.9, 65.9,70.8,70.8,73.6,73.6,178,3.
ESI-HRMS:m/z=369.3325[M+H]+;
compound VI:
1H-NMR(400MHz,CDCl3)δ:1.32(s,3H),2.10~2.38(m,12H),3.64~3.76(m,6H), 4.01~4.10(m,2H),4.54~4.66(m,4H),5.12(s,1H),7.71(s,2H);
13CNMR(100MHz,CDCl3)δ:15.5,20.3,20.3,29.9,29.9,31.7,31.7,45.1,56.9, 56.9,72.6,72.6,73.8,73.8,128.2,128.2,132.5,132.5,138.7,141.9,153.3,179.7.
ESI-HRMS:m/z=575.0763[M+H]+;
a compound I:
1H-NMR(400MHz,DMSO-d6)δ:0.72(d,J=6.6Hz,3H),0.76(d,J=6.0Hz,3H),0.81 (d,J=6.0Hz,3H),0.88(d,J=6.0Hz,3H),0.97(d,J=6.6Hz,3H),1.03(s,3H),1.09~1.17 (m,2H),1.42(s,3H),1.51~1.59(m,6H),1.62(s,3H),1.74(s,3H),1.76(s,3H), 1.81~1.87(m,4H),1.91~1.95(m,4H),1.97~2.03(m,3H),2.05~2.08(m,4H),2.11~2.14 (m,4H),2.16~2.20(m,2H),2.23~2.26(t,J=4.6Hz,2H),2.34~2.69(m,3H),3.02(s,3H), 3.12(s,3H),3.16~3.29(m,5H),3.37~3.48(m,6H),3.61(d,J=11.4Hz,1H),3.63~3.66 (m,4H),3.69(dd,J=12.4、10.2Hz,2H),3.92(d,J=3.6Hz,1H),4.01~4.11(m,1H),4.15 (dd,J=12.4、10.2Hz,2H),4.21(br s,1H),4.35~4.47(m,1H),4.55(t,J=4.5Hz,2H), 4.58~4.66(m,4H),4.94(d,J=3.6Hz,1H),4.96~5.07(m,1H),5.11(d,J=10.2Hz,1H), 5.31(d,J=4.2Hz,1H),5.44(dd,J=14.4、10.2Hz,1H),5.66(S,1H),6.10~6.15(m,2H), 6.23(t,J=10.2Hz,1H),6.38(dd,J=13.8、11.4Hz,1H),6.62(s,1H);
13CNMR(100MHz,DMSO-d6)δ:11.2,13.7,14.2,15.6,15.9,16.8,17.4,20.7,20.8,21.0,22.9,24.9,26.6,27.4,28.6,28.7,29.54,29.6,30.1,30.7,31.3,33.8, 34.2,35.8,35.9,36.7,38.8,39.5,40.2,40.3,40.5,43.8,44.8,45.4,50.7,51.3, 56.4,57.7,58.0,64.3,64.4,66.9,70.5,70.6,73.1,73.2,74.1,75.4,75.5,76.7, 76.7,80.8,82.5,86.0,99.4,125.1,127.8,130.7,132.9,137.4,138.2,139.8,167.3, 169.6,174.6,175.7,199.4,208.3,211.5.
ESI-HRMS:m/z=1263.7126[M+H]+;
when R1 is propyl and n is 0
Example 5
Synthesis of compound IV:
under the protection of nitrogen, adding a compound II (20.82g, 0.10mol) and a compound III (16.11g, 0.12mol) into 30ml of dichloromethane, controlling the temperature to be 5 ℃, adding sodium hydride (5.28g, 0.22mol), raising the temperature to room temperature for reaction after the addition is finished, detecting by TLC, after the reaction is finished, carrying out suction filtration, and carrying out reduced pressure concentration to obtain a compound IV, wherein the yield is 97.1%, and the purity is 99.75%.
Synthesis of Compound VI:
compound IV (34.13g, 0.11mol) and N, N-diisopropylethylamine (38.78g, 0.3mol) were dissolved in 120mL of toluene, compound V (24.39g,0.10mol) was added thereto, the temperature was controlled at 35 ℃ and TLC detection was performed, after the reaction was completed, filtration and concentration under reduced pressure were carried out to obtain compound VI in 97.5% yield and 99.71% purity.
Synthesis of Compound I:
under the protection of nitrogen, adding a compound VII (45.74g, 0.05mol) and a compound VI (31.06g, 0.06mol) into 300mL of dichloromethane, stirring and dissolving, adding triethylamine (20.24g, 0.20mol), controlling the temperature to 10 ℃ after dissolving, detecting by TLC (thin layer chromatography), adding trichloromethane for diluting after the reaction is finished, drying by anhydrous sodium sulfate, and concentrating under reduced pressure to obtain a compound I with the yield of 95.7% and the purity of 99.87%.
Compound IV:
1H-NMR(400MHz,CDCl3)δ:1.01(t,J=4.0Hz,3H),1.37(s,3H),1.54(m,2H),1.77 (d,2H),3.22~3.41(m,2H),3.65~3.79(m,6H),4.27~4.40(m,4H),12.11(s,1H);
13CNMR(100MHz,CDCl3)δ:15.2,15.4,16.6,32.8,45.7,70.4,70.4,71.3,71.3, 74.0,74.0,178.9.
ESI-HRMS:m/z=310.2836[M+H]+;
compound VI:
1H-NMR(400MHz,CDCl3)δ:1.01(t,J=4.0Hz,3H),1.34(s,3H),1.57(m,2H),1.79 (d,2H),3.23~3.38(m,2H),3.64~3.81(m,6H),4.23~4.37(m,4H),7.66(s,2H);
13CNMR(100MHz,CDCl3)δ:15.1,15.4,16.7,31.9,42.7,60.5,60.5,72.0,72.0, 73.1,73.1,128.4,128.4,133.3,138.2,183.2,143.1,151.9,178.7;
ESI-HRMS:m/z=517.0324[M+H]+;
a compound I:
1H-NMR(400MHz,DMSO-d6)δ:0.71(d,J=6.6Hz,3H),0.79(d,J=6.0Hz,3H),0.81 (d,J=6.0Hz,3H),0.86(d,J=6.0Hz,3H),0.93(t,J=4.0Hz,3H),0.97(d,J=6.6Hz,3H), 1.10(s,3H),1.11~1.18(m,2H),1.32~1.37(m,2H),1.42(s,3H),1.52~1.59(m,6H), 1.64(s,3H),1.71(d,J=4.2Hz,2H),1.75(s,3H),1.79(s,3H),1.92~2.02(m,3H), 2.14~2.21(m,2H),2.23~2.27(t,J=4.6Hz,2H),2.36~2.74(m,3H),3.06(s,3H),3.12 (s,3H),3.15~3.33(m,5H),3.38~3.50(m,6H),3.60(d,J=11.4Hz,1H),3.66(dd,J=12.4、 10.2Hz,2H),3.71~3.77(m,4H),3.80~3.84(m,4H),3.96(d,J=3.6Hz,1H),4.05~4.12 (m,1H),4.17(dd,J=12.4、10.2Hz,2H),4.22(br s,1H),4.36~4.45(m,1H),4.53 (t,J=4.5Hz,2H),4.58~4.64(m,4H),4.93(d,J=3.6Hz,1H),4.97~5.08(m,1H),5.15 (d,J=10.2Hz,1H),5.31(d,J=4.2Hz,1H),5.44(dd,J=14.4、10.2Hz,1H),6.11~6.16(m,2H), 6.23(t,J=10.2Hz,1H),6.37(dd,J=13.8、11.4Hz,1H),6.61(s,1H);
13CNMR(100MHz,DMSO-d6)δ:10.4,12.7,14.1,15.0,15.3,15.8,16.7,16.9, 17.3,20.6,22.4,24.5,25.7,26.3,27.1,29.6,30.2,31.1,32.8,33.4,33.8,35.5, 35.6,36.5,38.8,39.6,40.1,40.3,40.5,45.0,45.4,50.3,51.1,56.6,57.9,58.1, 60.6,60.6,64.3,64.3,66.8,72.6,72.5,73.2,73.2,74.4,76.7,76.7,80.9,82.2, 85.6,99.5,125.3,127.7,131.1,132.9,137.4,138.0,139.6,167.1,169.6,174.6, 175.7,199.4,208.1,211.3.
ESI-HRMS:m/z=1219.6831[M+H]+
when R1 is propyl and n is 3
Example 6
Synthesis of compound IV:
under the protection of nitrogen, adding the compound II (29.24g, 0.10mol) and the compound III (16.11g, 0.12mol) into 30ml of tetrahydrofuran, controlling the temperature at 0 ℃, adding sodium hydride (5.28g, 0.22mol), raising the temperature to room temperature for reaction after the addition is finished, detecting by TLC, after the reaction is finished, carrying out suction filtration and reduced pressure concentration to obtain the compound IV, wherein the yield is 98.1 percent, and the purity is 99.80 percent.
Synthesis of Compound VI:
compound IV (43.38, 0.11mol) and N, N-diisopropylethylamine (38.78g, 0.3mol) were dissolved in 120mL of dichloromethane, and Compound V (24.39g,0.10mol) was added thereto, the temperature was controlled at 30 ℃ and TLC detection was performed, after the reaction was completed, filtration and concentration under reduced pressure were carried out to give Compound VI in 98.5% yield and 99.78% purity.
Synthesis of Compound I:
under the protection of nitrogen, adding a compound VII (45.74g, 0.05mol) and a compound VI (36.11g, 0.06mol) into 300mL of dichloromethane, stirring and dissolving, adding 4-dimethylaminopyridine (24.44g, 0.20mol), controlling the temperature after dissolving and clearing at 5 ℃, 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 96.5% and the purity is 99.91%.
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=395.3115[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=602.4172[M+H]+。
a compound I:
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(br s,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=1291.5603[M+H]+。
Claims (10)
3. The preparation method according to claim 2, characterized in that the method 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.
4. The preparation method according to claim 3, wherein the organic base is selected from one of N, N-diisopropylethylamine, triethylamine, 2, 6-lutidine, 4-dimethylaminopyridine and N-methylmorpholine, or a combination thereof.
5. The preparation method according to claim 3, wherein the organic solvent A is selected from one of dichloromethane, N-dimethylformamide, chloroform, tetrahydrofuran, toluene, dioxane, or a combination thereof.
6. The preparation method according to claim 3, wherein the feeding molar ratio of the compound VII and the organic base is 1: 3.0-6.0.
7. The preparation method according to claim 3, wherein the molar ratio of the compound VII to the compound VI is 1: 1.0-2.0.
8. The preparation method according to claim 3, wherein the solvent B is one of dichloromethane, chloroform and ethyl acetate or a combination thereof.
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