CN117447307A - Preparation method of Tapinarof - Google Patents
Preparation method of Tapinarof Download PDFInfo
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- CN117447307A CN117447307A CN202311438071.5A CN202311438071A CN117447307A CN 117447307 A CN117447307 A CN 117447307A CN 202311438071 A CN202311438071 A CN 202311438071A CN 117447307 A CN117447307 A CN 117447307A
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- tapinarof
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- ZISJNXNHJRQYJO-CMDGGOBGSA-N 5-[(e)-2-phenylethenyl]-2-propan-2-ylbenzene-1,3-diol Chemical compound C1=C(O)C(C(C)C)=C(O)C=C1\C=C\C1=CC=CC=C1 ZISJNXNHJRQYJO-CMDGGOBGSA-N 0.000 title claims abstract description 21
- 229940070118 tapinarof Drugs 0.000 title claims abstract description 20
- 238000002360 preparation method Methods 0.000 title description 6
- 238000006243 chemical reaction Methods 0.000 claims abstract description 23
- 238000000034 method Methods 0.000 claims abstract description 21
- 150000001875 compounds Chemical class 0.000 claims abstract description 10
- OBXSGRKNCOCTTM-UHFFFAOYSA-N benzyl diethyl phosphate Chemical compound CCOP(=O)(OCC)OCC1=CC=CC=C1 OBXSGRKNCOCTTM-UHFFFAOYSA-N 0.000 claims abstract description 6
- QPUSANCBJDDXSA-UHFFFAOYSA-N ethanethiol;sodium Chemical compound [Na].CCS QPUSANCBJDDXSA-UHFFFAOYSA-N 0.000 claims abstract description 6
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims abstract description 6
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 claims description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 12
- 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 claims description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 8
- 230000015572 biosynthetic process Effects 0.000 claims description 7
- 238000003786 synthesis reaction Methods 0.000 claims description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 6
- IBXMKLPFLZYRQZ-UHFFFAOYSA-N 1,5-diphenylpenta-1,4-dien-3-one;palladium Chemical compound [Pd].[Pd].C=1C=CC=CC=1C=CC(=O)C=CC1=CC=CC=C1 IBXMKLPFLZYRQZ-UHFFFAOYSA-N 0.000 claims description 5
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 5
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 4
- 229910052757 nitrogen Inorganic materials 0.000 claims description 4
- 229910052700 potassium Inorganic materials 0.000 claims description 4
- 239000011591 potassium Substances 0.000 claims description 4
- 238000001953 recrystallisation Methods 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 4
- 238000003756 stirring Methods 0.000 claims description 4
- PBIMIGNDTBRRPI-UHFFFAOYSA-N trifluoro borate Chemical compound FOB(OF)OF PBIMIGNDTBRRPI-UHFFFAOYSA-N 0.000 claims description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 3
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 3
- 230000020477 pH reduction Effects 0.000 claims description 2
- 238000001308 synthesis method Methods 0.000 claims description 2
- -1 isopropyl potassium trifluoroborate Chemical compound 0.000 abstract description 6
- 239000000126 substance Substances 0.000 abstract description 6
- 238000009776 industrial production Methods 0.000 abstract description 4
- 238000010520 demethylation reaction Methods 0.000 abstract description 2
- 239000002994 raw material Substances 0.000 abstract description 2
- UGBJRYUNSXFPOX-UHFFFAOYSA-N 4-bromo-3,5-dimethoxybenzaldehyde Chemical compound COC1=CC(C=O)=CC(OC)=C1Br UGBJRYUNSXFPOX-UHFFFAOYSA-N 0.000 abstract 1
- 229940079593 drug Drugs 0.000 abstract 1
- 239000003814 drug Substances 0.000 abstract 1
- 239000012467 final product Substances 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- 238000001514 detection method Methods 0.000 description 5
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 description 4
- 239000007858 starting material Substances 0.000 description 4
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 3
- 238000012544 monitoring process Methods 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 238000001228 spectrum Methods 0.000 description 3
- 238000000967 suction filtration Methods 0.000 description 3
- 231100000331 toxic Toxicity 0.000 description 3
- 230000002588 toxic effect Effects 0.000 description 3
- UYEMGAFJOZZIFP-UHFFFAOYSA-N 3,5-dihydroxybenzoic acid Chemical compound OC(=O)C1=CC(O)=CC(O)=C1 UYEMGAFJOZZIFP-UHFFFAOYSA-N 0.000 description 2
- VYZAMTAEIAYCRO-UHFFFAOYSA-N Chromium Chemical compound [Cr] VYZAMTAEIAYCRO-UHFFFAOYSA-N 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 229910052804 chromium Inorganic materials 0.000 description 2
- 239000011651 chromium Substances 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- VAYGXNSJCAHWJZ-UHFFFAOYSA-N dimethyl sulfate Chemical compound COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 230000007613 environmental effect Effects 0.000 description 2
- 239000012065 filter cake Substances 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000012280 lithium aluminium hydride Substances 0.000 description 2
- XONPDZSGENTBNJ-UHFFFAOYSA-N molecular hydrogen;sodium Chemical compound [Na].[H][H] XONPDZSGENTBNJ-UHFFFAOYSA-N 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- RLCLASQCAPXVLM-NSHDSACASA-N CC(C)n1c(=O)cc(N[C@@H](C)c2ccccc2)[nH]c1=O Chemical compound CC(C)n1c(=O)cc(N[C@@H](C)c2ccccc2)[nH]c1=O RLCLASQCAPXVLM-NSHDSACASA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 1
- 201000004681 Psoriasis Diseases 0.000 description 1
- 238000006069 Suzuki reaction reaction Methods 0.000 description 1
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 230000001363 autoimmune Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 230000017858 demethylation Effects 0.000 description 1
- 230000008034 disappearance Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000000383 hazardous chemical Substances 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 229940069673 mavacamten Drugs 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 229940075993 receptor modulator Drugs 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C37/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring
- C07C37/01—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by replacing functional groups bound to a six-membered aromatic ring by hydroxy groups, e.g. by hydrolysis
- C07C37/055—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by replacing functional groups bound to a six-membered aromatic ring by hydroxy groups, e.g. by hydrolysis the substituted group being bound to oxygen, e.g. ether group
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/06—Antipsoriatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
- C07C41/01—Preparation of ethers
- C07C41/18—Preparation of ethers by reactions not forming ether-oxygen bonds
- C07C41/30—Preparation of ethers by reactions not forming ether-oxygen bonds by increasing the number of carbon atoms, e.g. by oligomerisation
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
- C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
- C07C45/68—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Medicinal Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Chemical & Material Sciences (AREA)
- Immunology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Engineering & Computer Science (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Dermatology (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to a Tapinarof, in particular to a novel method for preparing the Tapinarof. The method comprises the following steps: 1) Compound I (chemical name: 4-bromo-3, 5-dimethoxy benzaldehyde) and isopropyl potassium trifluoroborate to obtain intermediate IIThe method comprises the steps of carrying out a first treatment on the surface of the 2) Reacting the intermediate II with diethyl benzyl phosphate under the action of potassium tert-butoxide to obtain an intermediate III; 3) And (3) under the action of sodium ethanethiol, carrying out a demethylation reaction on the intermediate III to obtain a final product Tapinarof. The process route provided by the invention has the advantages that: the method has the advantages of short route, low-cost and easily-obtained raw materials, simple and convenient operation, mild conditions, high reaction yield, environment friendliness and easy industrial production, and avoids the use of dangerous drastic drugs and supervision dangerous chemicals.
Description
Technical Field
The invention relates to a synthesis method of Tapinarof, in particular to a novel method for preparing Tapinarof.
Background
Mavacamten (trade name)) Is an aromatic hydrocarbon receptor modulator of 'first-in-class', plays an important role in regulating autoimmune reaction, and is approved to be marketed by FDA in 5/23 of 2022 for the local treatment of adult plaque psoriasis. The CAS registry number is 79338-84-4, and the structural formula is shown below.
At present, only patent US20080255245 reports the synthetic route of Tapinarof, and the starting material 3, 5-dihydroxybenzoic acid is prepared with the Tapinarof through 6 steps of chemical reactions as shown below.
The technical route has the following defects: 1) In the reaction step, the method is used for monitoring extremely toxic dangerous chemicals, such as dimethyl sulfate, lithium aluminum hydride, sodium hydrogen, organic chromium reagents, boron tribromide and the like, has poor use and transportation convenience, has great harm to human bodies and the environment, and is not beneficial to the amplification reaction; 2) The reaction conditions are harsh, the reaction time is long, for example, the isopropyl process in the second step needs 7 days, and the final demethylation step needs to be carried out at-78 ℃; 3) The total reaction yield is only 26.8%, the atom economy is poor, the post-treatment is complex, more waste liquid is generated, and the environmental protection and the industrial production requirements are not facilitated.
Disclosure of Invention
In order to overcome the defects that the yield is low in the technical route and the extremely toxic supervision hazardous chemical is used at the same time, which is unfavorable for environmental protection and industrial production, the invention provides a novel method for Tapinarof synthesis, which adopts the following technical route:
the method comprises the following operation steps:
s1 Synthesis of Compound II
Dissolving the compound I in dioxane, adding potassium isopropyl trifluoroborate, dibenzylidene acetone dipalladium, and carrying out nitrogen protection reaction to obtain a compound II;
s2: synthesis of Compound III
Dissolving the compound II in 2-methyltetrahydrofuran, adding potassium tert-butoxide and diethyl benzyl phosphate, and reacting to obtain a compound III;
s3: synthesis of Tapinarof
Dissolving the compound III in ethanol, adding sodium ethanethiol, stirring for reaction, and performing acidification and recrystallization to obtain Tapinarof.
Wherein, in the step S1, the reaction temperature is 80 ℃, and the compound I: potassium isopropyl trifluoroborate: the molar ratio of the tri dibenzylidene acetone dipalladium is 1:1:0.05
Wherein, compound II in step S2: potassium tert-butoxide: the molar ratio of the diethyl benzyl phosphate is 1:2:1, the reaction temperature was 70 ℃.
Wherein, in the step S3, the reaction temperature is 70 ℃; compound III: the molar ratio of the sodium ethanethiol is 1:3; the acidified solution is concentrated hydrochloric acid, and the recrystallization solvent is ethanol.
Advantageous effects
1. When the SUZUKI reaction is carried out on the compound I by adopting a starting material completely different from the prior art, the required target product is difficult to prepare by adopting conventional coupling reaction conditions due to larger steric hindrance of bromine, so that the inventor obtains that the compound II can be prepared in high yield by adopting the protection reaction of isopropyl potassium trifluoroborate, dibenzylideneacetone dipalladium and nitrogen through experimental condition tests, wherein the important consideration is that the compound with small steric hindrance is isopropyl potassium trifluoroborate, and obviously, the aim of the invention cannot be realized by common isopropyl substituent.
2. The total yield of the invention is 81.9%, the purity is 100%, the total yield is far higher than the total yield (26.8%) of the prior art route, the unexpected technical effect is generated, and the invention is very suitable for industrial production.
3. The invention provides a novel method for preparing Tapinarof, which avoids monitoring extremely toxic dangerous chemicals such as dimethyl sulfate, lithium aluminum hydride, sodium hydrogen, organic chromium reagents, boron tribromide and the like, and greatly reduces the harm to human bodies and the environment.
4. The method has the advantages of short route, low-cost and easily-obtained raw materials, mild reaction conditions and better atom economy.
Drawings
FIG. 1 is a MS detection pattern of Tapinarof;
FIG. 2 is a hydrogen spectrum detection pattern of Tapinarof;
FIG. 3 is a carbon spectrum detection spectrum of Tapinarof.
Detailed Description
The following specific examples are provided to further illustrate the present invention in detail in order to make the objects, technical solutions and advantages of the present invention more apparent. The experimental methods in the invention are conventional methods unless otherwise specified. It should be understood that the specific embodiments described herein are for purposes of illustration only and are not intended to limit the scope of the invention.
The progress of the reaction of the present invention can be monitored by conventional monitoring methods in the art (e.g., TLC, HPLC or NMR), typically using the point of reaction at which the starting material has disappeared.
The chemicals and starting materials of the present invention were purchased from saen chemical technology (Shanghai) limited.
Example 1:
example 1 of the present invention provides a process for the preparation of intermediate II, which is synthesized as follows:
the preparation method specifically comprises the following steps:
compound I (100 g,408.04 mmol) was dissolved in dioxane (1.0L), potassium isopropyltrifluoroborate (61.20 g,408.04 mmol) was added, the dipalladium trisdibenzylideneacetone (18.68 g,20.40 mmol) was replaced 3 times with nitrogen, followed by stirring at 80℃for 10h, TLC detection was carried out until compound I disappeared, solvent was removed under reduced pressure, dichloromethane (2L x 3) and water (4L) were added, liquid extraction was carried out, thiourea resin (50 g) was added to the organic layer and stirred for 24 hours, suction filtration was carried out, solvent was removed under reduced pressure, MTBE was slurried to give 81g of pure compound II, yield 95.32%, ESI-MS (m/z): 209.1.
Example 2:
example 2 of the present invention provides a process for the preparation of intermediate III, which is synthesized as follows:
the preparation method specifically comprises the following steps:
compound II (81 g,388.94 mmol) was dissolved in 2-methyltetrahydrofuran (1.0L), potassium t-butoxide (87.29 g,777.89 mmol) was added, diethyl benzyl phosphate (88.77 g,388.94 mmol) was subsequently reacted at 70℃for 8h, TLC was used to detect the disappearance of compound II, water (5.0L) was added to the reaction system, a large amount of white solid was separated out, suction filtration was performed, and the filter cake was washed with dichloromethane (40 mL. Times.2) to obtain compound III as a white solid intermediate III 101g, yield 91.96%, ESI-MS (m/z): 283.2.
Example 3:
embodiment 3 of the present invention provides a method for preparing tapinaof:
intermediate III (101 g,357.67 mmol) is dissolved in ethanol (1.0L), sodium ethanethiol (90.25 g,1.07 mol) is added, stirring reaction is carried out for 12h at 70 ℃, TLC detection is carried out until the compound I disappears, cooling is carried out to room temperature, concentrated hydrochloric acid is added to adjust the pH of the solution to be 3-4, suction filtration is carried out, and the filter cake is recrystallized through ethanol (2.1L) to obtain the pure product of Tapinarof. The white solid obtained by the method was 85g, and the yield was 93.44%, ESI-MS (m/z, negative ion mode): 252.9.
1 H NMR(400MHz,DMSO)δ9.06(s,2H),7.57(d,J＝7.4Hz,2H),7.35(t,J＝7.6Hz,2H),7.24(t,J＝7.3Hz,1H),7.01(d,J＝16.3Hz,1H),6.89(d,J＝16.3Hz,1H),6.49(s,2H),3.50–3.40(m,1H),1.25(d,J＝7.1Hz,6H).
13 C NMR(101MHz,DMSO)δ156.87,137.51,135.24,129.41,129.13,127.84,127.21,126.83,120.60,105.64,24.16,21.07.
The above-described embodiments of the present invention do not limit the scope of the present invention. Any other corresponding changes and modifications made in accordance with the technical idea of the present invention shall be included in the scope of the claims of the present invention.
Claims (4)
1. The synthesis method of Tapinarof is characterized by comprising the following steps of:
the method comprises the following operation steps:
s1 Synthesis of Compound II
Dissolving the compound I in dioxane, adding potassium isopropyl trifluoroborate, dibenzylidene acetone dipalladium, and carrying out nitrogen protection reaction to obtain a compound II;
s2: synthesis of Compound III
Dissolving the compound II in 2-methyltetrahydrofuran, adding potassium tert-butoxide and diethyl benzyl phosphate, and reacting to obtain a compound III;
s3: synthesis of Tapinarof
Dissolving the compound III in ethanol, adding sodium ethanethiol, stirring for reaction, and performing acidification and recrystallization to obtain Tapinarof.
2. The method according to claim 1, wherein in step S1 the reaction temperature is 80 ℃, compound I: potassium isopropyl trifluoroborate: the molar ratio of the tri dibenzylidene acetone dipalladium is 1:1:0.05.
3. the method according to claim 1, wherein in step S2, compound II: potassium tert-butoxide: the molar ratio of the diethyl benzyl phosphate is 1:2:1, the reaction temperature was 70 ℃.
4. The method according to claim 1, wherein the reaction temperature in step S3 is 70 ℃; compound III: the molar ratio of the sodium ethanethiol is 1:3; the acidified solution is concentrated hydrochloric acid, and the recrystallization solvent is ethanol.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202311438071.5A CN117447307A (en) | 2023-11-01 | 2023-11-01 | Preparation method of Tapinarof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202311438071.5A CN117447307A (en) | 2023-11-01 | 2023-11-01 | Preparation method of Tapinarof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN117447307A true CN117447307A (en) | 2024-01-26 |
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| CN202311438071.5A Pending CN117447307A (en) | 2023-11-01 | 2023-11-01 | Preparation method of Tapinarof |
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| Country | Link |
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| CN (1) | CN117447307A (en) |
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2023
- 2023-11-01 CN CN202311438071.5A patent/CN117447307A/en active Pending
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