CN117384233A - Process for preparing diterpene lactone compounds - Google Patents
Process for preparing diterpene lactone compounds Download PDFInfo
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- CN117384233A CN117384233A CN202311267970.3A CN202311267970A CN117384233A CN 117384233 A CN117384233 A CN 117384233A CN 202311267970 A CN202311267970 A CN 202311267970A CN 117384233 A CN117384233 A CN 117384233A
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- 229930004069 diterpene Natural products 0.000 title claims abstract description 21
- -1 diterpene lactone compounds Chemical class 0.000 title claims abstract description 21
- 238000004519 manufacturing process Methods 0.000 title claims description 11
- 238000000034 method Methods 0.000 claims abstract description 34
- 229940125782 compound 2 Drugs 0.000 claims description 29
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 25
- 239000002904 solvent Substances 0.000 claims description 21
- OSVHLUXLWQLPIY-KBAYOESNSA-N butyl 2-[(6aR,9R,10aR)-1-hydroxy-9-(hydroxymethyl)-6,6-dimethyl-6a,7,8,9,10,10a-hexahydrobenzo[c]chromen-3-yl]-2-methylpropanoate Chemical compound C(CCC)OC(C(C)(C)C1=CC(=C2[C@H]3[C@H](C(OC2=C1)(C)C)CC[C@H](C3)CO)O)=O OSVHLUXLWQLPIY-KBAYOESNSA-N 0.000 claims description 20
- 150000001875 compounds Chemical class 0.000 claims description 11
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 10
- 239000007800 oxidant agent Substances 0.000 claims description 10
- 230000001590 oxidative effect Effects 0.000 claims description 10
- FANCTJAFZSYTIS-IQUVVAJASA-N (1r,3s,5z)-5-[(2e)-2-[(1r,3as,7ar)-7a-methyl-1-[(2r)-4-(phenylsulfonimidoyl)butan-2-yl]-2,3,3a,5,6,7-hexahydro-1h-inden-4-ylidene]ethylidene]-4-methylidenecyclohexane-1,3-diol Chemical compound C([C@@H](C)[C@@H]1[C@]2(CCCC(/[C@@H]2CC1)=C\C=C\1C([C@@H](O)C[C@H](O)C/1)=C)C)CS(=N)(=O)C1=CC=CC=C1 FANCTJAFZSYTIS-IQUVVAJASA-N 0.000 claims description 9
- 229940125904 compound 1 Drugs 0.000 claims description 9
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 8
- 239000012298 atmosphere Substances 0.000 claims description 8
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 8
- 239000003054 catalyst Substances 0.000 claims description 8
- 239000001301 oxygen Substances 0.000 claims description 8
- 229910052760 oxygen Inorganic materials 0.000 claims description 8
- 229910052763 palladium Inorganic materials 0.000 claims description 8
- 125000006527 (C1-C5) alkyl group Chemical group 0.000 claims description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 6
- 125000002252 acyl group Chemical group 0.000 claims description 6
- 230000001476 alcoholic effect Effects 0.000 claims description 6
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- 229940117975 chromium trioxide Drugs 0.000 claims description 4
- WGLPBDUCMAPZCE-UHFFFAOYSA-N chromium trioxide Inorganic materials O=[Cr](=O)=O WGLPBDUCMAPZCE-UHFFFAOYSA-N 0.000 claims description 4
- GAMDZJFZMJECOS-UHFFFAOYSA-N chromium(6+);oxygen(2-) Chemical group [O-2].[O-2].[O-2].[Cr+6] GAMDZJFZMJECOS-UHFFFAOYSA-N 0.000 claims description 4
- 101150003085 Pdcl gene Proteins 0.000 claims description 3
- 125000001188 haloalkyl group Chemical group 0.000 claims description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 3
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 150000002367 halogens Chemical class 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- 125000001424 substituent group Chemical group 0.000 claims description 2
- 238000002360 preparation method Methods 0.000 abstract description 22
- DFBIRQPKNDILPW-CIVMWXNOSA-N Triptolide Chemical compound O=C1OCC([C@@H]2C3)=C1CC[C@]2(C)[C@]12O[C@H]1[C@@H]1O[C@]1(C(C)C)[C@@H](O)[C@]21[C@H]3O1 DFBIRQPKNDILPW-CIVMWXNOSA-N 0.000 abstract description 19
- YKUJZZHGTWVWHA-UHFFFAOYSA-N triptolide Natural products COC12CC3OC3(C(C)C)C(O)C14OC4CC5C6=C(CCC25C)C(=O)OC6 YKUJZZHGTWVWHA-UHFFFAOYSA-N 0.000 abstract description 18
- 125000002887 hydroxy group Chemical group [H]O* 0.000 abstract description 15
- 238000006243 chemical reaction Methods 0.000 abstract description 11
- 125000003545 alkoxy group Chemical group 0.000 abstract description 10
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 abstract description 4
- 238000001212 derivatisation Methods 0.000 abstract description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 18
- 230000000052 comparative effect Effects 0.000 description 10
- 239000000243 solution Substances 0.000 description 9
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- 101100038180 Caenorhabditis briggsae rpb-1 gene Proteins 0.000 description 6
- 101100038181 Caenorhabditis elegans ama-1 gene Proteins 0.000 description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 239000001257 hydrogen Substances 0.000 description 6
- 229910052739 hydrogen Inorganic materials 0.000 description 6
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 6
- 238000001228 spectrum Methods 0.000 description 6
- 239000002253 acid Substances 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 238000004440 column chromatography Methods 0.000 description 4
- 239000011259 mixed solution Substances 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 239000000758 substrate Substances 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- 230000004071 biological effect Effects 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 108090000623 proteins and genes Proteins 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 238000012216 screening Methods 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 238000013518 transcription Methods 0.000 description 3
- 230000035897 transcription Effects 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- 230000005778 DNA damage Effects 0.000 description 2
- 231100000277 DNA damage Toxicity 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 241000830536 Tripterygium wilfordii Species 0.000 description 2
- 230000015556 catabolic process Effects 0.000 description 2
- 238000006731 degradation reaction Methods 0.000 description 2
- 238000013461 design Methods 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 230000026731 phosphorylation Effects 0.000 description 2
- 238000006366 phosphorylation reaction Methods 0.000 description 2
- 230000001737 promoting effect Effects 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 235000015398 thunder god vine Nutrition 0.000 description 2
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 2
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- 108091000080 Phosphotransferase Proteins 0.000 description 1
- 102000019014 Positive Transcriptional Elongation Factor B Human genes 0.000 description 1
- 108010012271 Positive Transcriptional Elongation Factor B Proteins 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 102000009572 RNA Polymerase II Human genes 0.000 description 1
- 108010009460 RNA Polymerase II Proteins 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 125000001475 halogen functional group Chemical group 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 230000009456 molecular mechanism Effects 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 230000000865 phosphorylative effect Effects 0.000 description 1
- 102000020233 phosphotransferase Human genes 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- USHAGKDGDHPEEY-UHFFFAOYSA-L potassium persulfate Chemical compound [K+].[K+].[O-]S(=O)(=O)OOS([O-])(=O)=O USHAGKDGDHPEEY-UHFFFAOYSA-L 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000005556 structure-activity relationship Methods 0.000 description 1
- 230000034512 ubiquitination Effects 0.000 description 1
- 238000010798 ubiquitination Methods 0.000 description 1
- 238000011144 upstream manufacturing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J73/00—Steroids in which the cyclopenta[a]hydrophenanthrene skeleton has been modified by substitution of one or two carbon atoms by hetero atoms
- C07J73/001—Steroids in which the cyclopenta[a]hydrophenanthrene skeleton has been modified by substitution of one or two carbon atoms by hetero atoms by one hetero atom
- C07J73/003—Steroids in which the cyclopenta[a]hydrophenanthrene skeleton has been modified by substitution of one or two carbon atoms by hetero atoms by one hetero atom by oxygen as hetero atom
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a preparation method of diterpene lactone compounds, belonging to the field of organic chemistry. The invention provides a method for preparing diterpene lactone compounds with carbonyl, hydroxyl or alkoxy introduced into specific reaction sites, which can directly introduce hydroxyl or alkoxy into C14 position and obtain excellent yield. The invention provides a brand-new route for preparing triptolide or derivatives thereof, and provides a new route for derivatization of the triptolide C14 site.
Description
Technical Field
The invention relates to the field of organic chemistry, in particular to a preparation method of diterpene lactone compounds.
Background
Tripterygium wilfordii is a traditional Chinese medicine with long-term and wide application history. Triptolide and triptolide are main active ingredients of Tripterygium wilfordii.
The research on the molecular mechanism of triptolide for inhibiting the transcription of a wide range of genes was conducted by the institute of pharmaceutical research on Shanghai, national institute of sciences Jiang. It was found that triptolide inhibits transcription of genes by promoting phosphorylation of the largest and most prominent functional subunit Rpb1 in RNA polymerase II, followed by ubiquitination degradation of Rpb 1. Rpb1 upstream kinase PTEF-b exerts a positive regulatory effect during triptolide-induced phosphorylation of Rpb 1. It has also been found that triptolide can induce DNA damage. These studies suggest that triptolide inhibits broad-spectrum gene transcription by causing DNA damage to cells, thereby activating P-TEFb, phosphorylating Rpb1, and causing degradation of Rpb 1.
According to the report in J.org.chem.2000,65,2208-2217, both compound 3a and compound 3b are important intermediates for the synthesis of triptolide or triptolide.
In addition, referring to fig. 4, the chemical engineering university of Beijing, chemie, cheng Long, indicates that the hydroxyl group at the C14 position is an important active group in its Shuoshi 'design, synthesis and biological activity research of triptolide derivatives', and a series of compounds with biological activity can be obtained after derivatization.
However, in the prior art, the hydroxyl or alkoxy at the C14 position is self-contained in the starting material, and the method of directly introducing the hydroxyl or alkoxy at the C14 position is lacking, which not only increases the production cost of the intermediate such as the compound 3a or 3b, but also brings difficulty to the C14 hydroxyl derivative of triptolide.
Disclosure of Invention
The present invention has been made to solve the above problems, and an object of the present invention is to provide a method for producing a diterpene lactone compound capable of introducing a carbonyl group, a hydroxyl group or an alkoxy group at a specific reaction site.
The application comprises the following three groups of technical schemes.
Scheme a:
the process for producing diterpene lactone compounds has the following characteristics:
wherein R is a C1-C5 alkyl group,
the method comprises the following steps:
step 1, reacting a compound 1 with an oxidant to obtain a compound 2;
step 2, under the atmosphere of oxygen, under the condition of palladium catalyst,And in the presence of a solvent, converting compound 2 into compound 3a or compound 3b,
R 1 ，R 2 each independently selected from H, acyl or sulfonyl, and R 1 ，R 2 And not H at the same time.
In the above preparation method, the acyl group is-COR 3 Sulfonyl is-SO 2 R 4 The method comprises the steps of carrying out a first treatment on the surface of the Wherein R is 3 、R 4 Each independently selected from C1-C5 alkyl, C1-C5 halo (F, cl, br, I) alkyl, substituted or substituted phenyl, the substituents being halogen, C1-5 alkyl, C1-C5 haloalkyl.
In the above preparation method, the oxidant in step 1 is chromium trioxide.
In the above preparation method, the process in step 1 specifically includes: respectively dissolving a compound 1 and an oxidant in a mixed solution of acetic acid/water to obtain a substrate solution and an acid solution; the substrate solution is mixed with the acid solution and reacted for a period of time, preferably 3 to 10 hours, at 10 to 30 ℃.
In the preparation method, the molar ratio of the compound 1 to the oxidant is 1.8-2.5:1. specifically, the method comprises the following steps of: 1.
in the above preparation method, the concentration of the substrate solution is 3-5mmol/mL.
In the above preparation method, the concentration of the acid solution is 0.2-0.5mmol/mL.
In the preparation method, the volume ratio of the acetic acid to the water mixed solution is (8-10): 1. specifically, optional 9:1.
in the above preparation method, step 2 is describedIs an oxidant, and is specifically selected from any one or more of the following compounds:
in the above-mentioned method of preparation,the molar ratio of the compound to the compound 2 is 2-4:1.
in the above preparation method, the palladium catalyst in step 2 is selected from any one or more of the following: pdCl 2 、Pd(OAc) 2 、Pd(PPh 3 ) 4 Or Pd (or) 2 (dba) 3 。
In the above preparation method, the molar ratio of the palladium catalyst to the compound 2 in the step 2 is (0.1 to 0.3): 1.
in the preparation method, the dosage of the solvent in the step 2 relative to the compound 2 is 40-60 mL/g; specifically, 50mL/g is selected.
In the above preparation method, when the solvent in step 2 is an alcohol solvent ROH, the compound 2 is converted into the compound 3a.
In the above preparation method, when the solvent in step 2 is a non-alcoholic solvent, compound 2 is converted into compound 3b.
In the above preparation method, the non-alcoholic solvent is selected from any one or more of 1, 2-dichloroethane, dichloromethane, chloroform, tetrahydrofuran and 2-methyltetrahydrofuran.
Scheme B:
the process for producing diterpene lactone compounds has the following characteristics:
the method comprises the following steps:
the compound 1 reacts with an oxidant to obtain a compound 2,
wherein the oxidant is chromium trioxide.
Scheme C:
the process for producing diterpene lactone compounds has the following characteristics:
wherein R is H or C1-C5 alkyl,
the method comprises the following steps:
under the atmosphere of oxygen, under the condition of palladium catalyst,And in the presence of a solvent, converting compound 2 into compound 3a or compound 3b,
R 1 ，R 2 independently of one another, from H, acyl or sulfonyl, and R 1 ，R 2 And not H at the same time.
Effects and effects of the invention
According to the diterpene lactone compound, a method capable of directly introducing hydroxyl or alkoxy at the C14 position is developed, and excellent yield (more than 77%) is obtained, so that a brand-new and efficient route for preparing triptolide or derivatives thereof is developed, and in addition, the method is favorable for providing a new route for derivatization of the C14 position of triptolide in the future.
Drawings
FIG. 1 is a hydrogen spectrum of compound 2 in example 1 of the present invention;
FIG. 2 is a hydrogen spectrum of compound 3b in example 2 of the present invention;
FIG. 3 is a hydrogen spectrum of compound 3a-1 in example 2 of the present invention;
FIG. 4 is a diagram of the structure-activity relationship of triptolide cited in the background of the invention from the studies of design, synthesis and biological Activity of triptolide derivatives.
Detailed Description
In order to make the technical means, the creation features, the achievement of the purpose and the effect of the present invention easy to understand, the present invention is specifically described below with reference to the embodiments and the drawings.
In the examples below, each of the raw materials was a commercially available product unless otherwise specified.
Example 1 ]
Preparation of Compound 2
This example provides a method for preparing compound 2, having the following reaction formula:
the method comprises the following steps:
6.21g of chromium trioxide (62.16 mmol,2.0 eq) was dissolved in a mixed solution of acetic acid/water (18 mL of acetic acid/2 mL of water) to obtain an acid solution.
9.2g of Compound 1 (31.08 mmol,1.0 eq) was added to a mixed solution of acetic acid/water (135 mL of acetic acid/15 mL of water) under a nitrogen atmosphere, the temperature was controlled to 0℃and the acid solution was added dropwise, the temperature was raised to 25℃after the completion of the dropwise addition, and the reaction was stirred for 5 hours.
50mL of methylene chloride was added for extraction, and the organic phase was taken and washed once with 60mL of water and 60mL of saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and subjected to column chromatography to obtain 7.15g of Compound 2 as a yellow solid in 74.1% yield.
The hydrogen spectrum of compound 2 is shown in figure 1.
LCMS:m/z(ESI),[M+H] + ＝311
1 H NMR(400MHz,CDCl 3 )δ7.95(d,J＝2.0Hz,1H),7.47(m,1H),7.41(d,J＝8.0Hz,1H),4.78(m,2H),3.23(s,1H),2.96(m,1H),2.79-2.73(m,2H),2.60(m,2H),2.51-2.38(m,1H),1.83(m,1H),1.28(s,3H),1.26(s,3H),1.16(s,3H).
Example 2 ]
Preparation of Compound 3b
This example provides a method for preparing compound 3b, which has the following reaction formula:
the method comprises the following steps:
200mg of Compound 2 (0.64 mmol,1.0 eq) are dissolved in 10ml of 1, 2-dichloroethane and 554.7mg are added(1.29 mmol,2.0 eq) and 14.4mg palladium acetate (0.064 mmol,0.1 eq) were heated to 80℃under an oxygen atmosphere and reacted with stirring for 16h. Cooling to room temperature, filtering with celite, washing with 1, 2-dichloroethane, collecting filtrate, concentrating under reduced pressure, and performing column chromatography to obtain 165.0mg of compound 3b as pale yellow solid with a yield of 79.0%.
The hydrogen spectrum of compound 3b is shown in FIG. 2.
LCMS:m/z(ESI),[M+H] + ＝327
1 H NMR(400MHz,CDCl 3 )δ8.16(s,1H),7.15(d,J＝8.0Hz,1H),6.88(d,J＝8.0Hz,1H),5.24(t,J＝8.8Hz,1H),4.79(m,2H),3.30(m,1H),2.79(d,J＝13.6Hz,1H),2.48(m,2H),2.42-2.33(m,2H),2.02-1.94(m,1H),1.66(m,2H),1.25(s,3H),1.23(d,J＝4.0Hz,3H),1.11(s,3H).
Example 3 ]
Preparation of Compound 3a-1
The present example provides a process for the preparation of compound 3a-1, having the following reaction scheme:
the method comprises the following steps:
200mg of Compound 2 (0.64 mmol,1.0 eq) are dissolved in 10mL of methanol, and 554.7mg are added(1.29 mmol,2.0 eq) and 14.4mg palladium acetate (0.064 mmol,0.1 eq) were heated to 80℃under an oxygen atmosphere and reacted with stirring for 16h. Cooling to room temperature, filtering with diatomite, washing with methanol, collecting filtrate, concentrating under reduced pressure, and performing column chromatography to obtain 168.0mg of compound 3a-1 as pale yellow solid with a yield of 77.1%.
The hydrogen spectrum of compound 3a-1 is shown in FIG. 3.
LCMS:m/z(ESI),[M+H]+＝341
1H NMR(400MHz,CDCl3)δ7.47(d,J＝8.0Hz,1H),7.20(d,J＝8.0Hz,1H),4.77(s,2H),3.83(s,3H),3.41(m,1H),3.14(d,J＝14.0Hz,1H),2.81(m,1H),2.71-2.50(m,3H),2.41(s,1H),1.82(m,1H),1.26(d,J＝6.8Hz,3H),1.20(d,J＝6.8Hz,3H),1.13(s,3H).
Comparative example 1 ]
Screening of the method for preparing Compound 3b
The preparation method of this comparative example was substantially the same as in example 2, except that in this comparative example, the reaction was carried out under atmospheric conditions. LCMS showed only trace compound 3b production.
Comparative example 2 ]
Screening of the method for preparing Compound 3b
100mg of Compound 2 (0.32 mmol,1.0 eq) was dissolved in 5mL of trifluoroacetic acid under nitrogen, 173mg of potassium persulfate (0.64 mmol,2.0 eq) and 6.8mg of palladium acetate (0.03 mmol,0.1 eq) and 0.5mL of trifluoroacetic anhydride were added, the temperature was raised to 80℃and stirred for 16h, and the sample was taken for LCMS, indicating no reaction.
Comparative example 3 ]
Screening of the method for preparing Compound 3b
100mg of Compound 2 (0.32 mmol,1.0 eq) were dissolved in 5mL of 1, 2-dichloromethane under nitrogen, 233.6mg of potassium peroxymonosulphonate (0.38 mmol,1.2 eq), 6.8mg of palladium acetate (0.03 mmol,0.1 eq) and 7.9mg of triphenylphosphine (0.03 mmol,0.1 eq) were added, the mixture was heated to 90℃and refluxed for 16h, and the sample was taken to LCMS, indicating unreacted.
Comparative example 4 ]
In this comparative example, an attempt was made to introduce a hydroxyl group directly at the C14 position using compound 1 as a starting material.
The experimental procedure was as follows:
200mg of Compound 1 (0.67 mmol,1.0 eq) are dissolved in 10ml of 1, 2-dichloroethane and 576.2mg are added(1.34 mmol,2.0 eq) and 15.0mg palladium acetate (0.067 mmol,0.1 eq) were heated to 80℃under oxygen atmosphere and reacted for 16h with stirring, the sample was taken for LCMS and no product was detected at C14-introduced hydroxy group.
Comparative example 5 ]
Referring to example 2, substrate compound 2 was replaced with compound 2'.
The present example provides a method for preparing compound 3b', the reaction formula is as follows:
the method comprises the following steps:
200mg of Compound 2' (0.745 mmol,1.0 eq) are dissolved in 10ml of 1, 2-dichloroethane and 640.7mg are added(1.49 mmol,2.0 eq) and 16.8mg palladium acetate (0.075 mmol,0.1 eq) were heated to 80℃under atmospheric conditions and the reaction stirred for 16h. Cooling to room temperature, filtering with celite, washing with 1, 2-dichloroethane, collecting the filtrate, concentrating under reduced pressure, and performing column chromatography to obtain 125.3mg of compound 3b', as pale yellow solid with a yield of 59.1%.
Effects and effects of the examples
According to the diterpene lactone compound in the embodiment, since a method capable of directly introducing hydroxyl or alkoxy at the C14 position is developed, a brand-new route for preparing triptolide or a triptolide derivative is developed, and in addition, the method is beneficial to providing a new route for derivatization of the C14 position of triptolide in the future.
In combination with examples 2-3 and comparative example 4, the applicant has unexpectedly found that the presence or absence of a carbonyl group at the C7 position is critical for the successful introduction of a hydroxyl or alkoxy group at C14. When the carbonyl group is present at the C7 position, the reaction of introducing the hydroxyl group or the alkyl group at the C14 position proceeds smoothly.
In combination with example 2 and comparative example 1, the applicant has unexpectedly found that the performance under an oxygen atmosphere is advantageous in promoting the smooth introduction of hydroxyl or alkoxy groups on C14.
In combination with examples 2 and 3, the applicant has unexpectedly found that the products formed after the oxidation reaction at the C14 position are closely related to the reaction solvent, the alkoxy groups being introduced at the C14 position when the solvent is an alcoholic solvent, and the hydroxyl groups being introduced at the C14 position when the solvent is a non-alcoholic solvent such as 1, 2-dichloroethane, tetrahydrofuran, etc.
The above examples are not intended to limit the scope of the invention nor the order of execution of the steps described. The present invention is obviously modified by a person skilled in the art in combination with the prior common general knowledge, and falls within the scope of protection defined by the claims of the present invention.
Claims (10)
1. A process for producing diterpene lactone compounds, which comprises:
wherein R is a C1-C5 alkyl group,
the method comprises the following steps:
step 1, reacting a compound 1 with an oxidant to obtain a compound 2;
step 2, under the atmosphere of oxygen, under the condition of palladium catalyst,And in the presence of a solvent, converting compound 2 into compound 3a or compound 3b,
R 1 ，R 2 independently of one another, from H, acyl or sulfonyl, and R 1 ，R 2 And not H at the same time.
2. The method for producing a diterpene lactone compound according to claim 1, wherein:
wherein the acyl group is-COR 3 Sulfonyl is-SO 2 R 4 ；R 3 、R 4 Each independently selected from C1-C5 alkyl, C1-C5 haloalkyl, substituted or unsubstituted phenyl, and the substituents are halogen, C1-5 alkyl, C1-C5 haloalkyl.
3. The method for producing a diterpene lactone compound according to claim 1, wherein:
wherein the palladium catalyst is selected from any one or more of the following compounds: pdCl 2 、Pd(OAc) 2 、Pd(PPh 3 ) 4 Or Pd (or) 2 (dba) 3 。
4. The method for producing a diterpene lactone compound according to claim 1, wherein:
wherein in step 2, when the solvent is ROH, compound 2 is converted to compound 3a.
5. The method for producing a diterpene lactone compound according to claim 1, wherein:
wherein in step 2, when the solvent is a non-alcoholic solvent, compound 2 is converted into compound 3b.
6. The process for producing a diterpene lactone compound according to claim 5, wherein,
wherein the non-alcohol solvent is selected from any one or more of 1, 2-dichloroethane, dichloromethane, chloroform, tetrahydrofuran and 2-methyltetrahydrofuran.
7. A process for producing diterpene lactone compounds, characterized by comprising,
the method comprises the following steps:
the compound 1 reacts with an oxidant to obtain a compound 2,
wherein the oxidant is chromium trioxide.
8. A process for producing diterpene lactone compounds, characterized by comprising,
wherein R is H or C1-C5 alkyl,
the method comprises the following steps:
under the atmosphere of oxygen, under the condition of palladium catalyst,And in the presence of a solvent, converting compound 2 into compound 3a or compound 3b,
R 1 ，R 2 independently of one another, from H, acyl or sulfonyl, and R 1 ，R 2 And not H at the same time.
9. The method for producing a diterpene lactone compound according to claim 8, wherein:
wherein, when the solvent is ROH, compound 2 is converted to compound 3a; when the solvent is a non-alcoholic solvent, compound 2 is converted into compound 3b.
10. The method for producing a diterpene lactone compound according to claim 8, wherein:
wherein,any one or more selected from the following compounds:
the palladium catalyst is selected from any one or more of the following compounds: pdCl 2 、Pd(OAc) 2 、Pd(PPh 3 ) 4 Or Pd (or) 2 (dba) 3 。
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