CN117164568A - Resmetirom intermediate and preparation method thereof as well as preparation method of intermediate III - Google Patents
Resmetirom intermediate and preparation method thereof as well as preparation method of intermediate III Download PDFInfo
- Publication number
- CN117164568A CN117164568A CN202311118581.4A CN202311118581A CN117164568A CN 117164568 A CN117164568 A CN 117164568A CN 202311118581 A CN202311118581 A CN 202311118581A CN 117164568 A CN117164568 A CN 117164568A
- Authority
- CN
- China
- Prior art keywords
- compound
- formula
- structure shown
- reaction
- preparation
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 238000002360 preparation method Methods 0.000 title claims abstract description 33
- FDBYIYFVSAHJLY-UHFFFAOYSA-N resmetirom Chemical compound N1C(=O)C(C(C)C)=CC(OC=2C(=CC(=CC=2Cl)N2C(NC(=O)C(C#N)=N2)=O)Cl)=N1 FDBYIYFVSAHJLY-UHFFFAOYSA-N 0.000 title claims abstract description 29
- 229940121486 resmetirom Drugs 0.000 title claims abstract description 24
- 238000006243 chemical reaction Methods 0.000 claims abstract description 46
- 238000006467 substitution reaction Methods 0.000 claims abstract description 18
- 238000010511 deprotection reaction Methods 0.000 claims abstract description 13
- 150000001875 compounds Chemical class 0.000 claims description 112
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 45
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 36
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 36
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 34
- 239000003960 organic solvent Substances 0.000 claims description 31
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 30
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 26
- 238000000034 method Methods 0.000 claims description 23
- 238000002156 mixing Methods 0.000 claims description 22
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 18
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 18
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 18
- 238000006460 hydrolysis reaction Methods 0.000 claims description 16
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 14
- 150000001408 amides Chemical class 0.000 claims description 14
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 13
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 13
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 11
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 claims description 10
- FGLBSLMDCBOPQK-UHFFFAOYSA-N 2-nitropropane Chemical compound CC(C)[N+]([O-])=O FGLBSLMDCBOPQK-UHFFFAOYSA-N 0.000 claims description 10
- KGEXISHTCZHGFT-UHFFFAOYSA-N 4-azaniumyl-2,6-dichlorophenolate Chemical compound NC1=CC(Cl)=C(O)C(Cl)=C1 KGEXISHTCZHGFT-UHFFFAOYSA-N 0.000 claims description 10
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 9
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 9
- BUDQDWGNQVEFAC-UHFFFAOYSA-N Dihydropyran Chemical compound C1COC=CC1 BUDQDWGNQVEFAC-UHFFFAOYSA-N 0.000 claims description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 9
- CHLCPTJLUJHDBO-UHFFFAOYSA-M sodium;benzenesulfinate Chemical compound [Na+].[O-]S(=O)C1=CC=CC=C1 CHLCPTJLUJHDBO-UHFFFAOYSA-M 0.000 claims description 9
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 9
- 150000007514 bases Chemical class 0.000 claims description 8
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 7
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 6
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 3
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 3
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 3
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 3
- 239000000543 intermediate Substances 0.000 abstract description 45
- 239000007787 solid Substances 0.000 abstract description 12
- SQGYOTSLMSWVJD-UHFFFAOYSA-N silver(1+) nitrate Chemical compound [Ag+].[O-]N(=O)=O SQGYOTSLMSWVJD-UHFFFAOYSA-N 0.000 abstract description 8
- 238000004519 manufacturing process Methods 0.000 abstract description 5
- 230000035484 reaction time Effects 0.000 abstract description 5
- 229910001961 silver nitrate Inorganic materials 0.000 abstract description 4
- 238000000746 purification Methods 0.000 abstract description 3
- 230000009286 beneficial effect Effects 0.000 abstract description 2
- 238000009776 industrial production Methods 0.000 abstract description 2
- 239000013067 intermediate product Substances 0.000 abstract description 2
- 239000012450 pharmaceutical intermediate Substances 0.000 abstract description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 30
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 24
- 238000005406 washing Methods 0.000 description 22
- 238000003756 stirring Methods 0.000 description 18
- 239000012046 mixed solvent Substances 0.000 description 14
- 239000000203 mixture Substances 0.000 description 13
- 238000001816 cooling Methods 0.000 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 description 11
- 238000001914 filtration Methods 0.000 description 10
- 239000012295 chemical reaction liquid Substances 0.000 description 8
- 238000001035 drying Methods 0.000 description 8
- 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 description 7
- 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 6
- 238000005160 1H NMR spectroscopy Methods 0.000 description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- DEQYTNZJHKPYEZ-UHFFFAOYSA-N ethyl acetate;heptane Chemical compound CCOC(C)=O.CCCCCCC DEQYTNZJHKPYEZ-UHFFFAOYSA-N 0.000 description 6
- 239000007788 liquid Substances 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 208000008338 non-alcoholic fatty liver disease Diseases 0.000 description 5
- 206010053219 non-alcoholic steatohepatitis Diseases 0.000 description 5
- 239000012265 solid product Substances 0.000 description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 4
- 238000005481 NMR spectroscopy Methods 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- 229910052739 hydrogen Inorganic materials 0.000 description 4
- 239000001257 hydrogen Substances 0.000 description 4
- 239000011259 mixed solution Substances 0.000 description 4
- 230000001105 regulatory effect Effects 0.000 description 4
- 238000001228 spectrum Methods 0.000 description 4
- 208000004930 Fatty Liver Diseases 0.000 description 3
- 206010019708 Hepatic steatosis Diseases 0.000 description 3
- 239000003513 alkali Substances 0.000 description 3
- 208000019425 cirrhosis of liver Diseases 0.000 description 3
- 208000010706 fatty liver disease Diseases 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 0.000 description 3
- 231100000240 steatosis hepatitis Toxicity 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- 229940126062 Compound A Drugs 0.000 description 2
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 description 2
- 206010016654 Fibrosis Diseases 0.000 description 2
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 2
- ROOXNKNUYICQNP-UHFFFAOYSA-N ammonium persulfate Chemical compound [NH4+].[NH4+].[O-]S(=O)(=O)OOS([O-])(=O)=O ROOXNKNUYICQNP-UHFFFAOYSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 230000007882 cirrhosis Effects 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- KQNPFQTWMSNSAP-UHFFFAOYSA-N isobutyric acid Chemical compound CC(C)C(O)=O KQNPFQTWMSNSAP-UHFFFAOYSA-N 0.000 description 2
- 210000004185 liver Anatomy 0.000 description 2
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 description 2
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- 229940123876 Thyroid hormone receptor beta agonist Drugs 0.000 description 1
- AUYYCJSJGJYCDS-LBPRGKRZSA-N Thyrolar Chemical class IC1=CC(C[C@H](N)C(O)=O)=CC(I)=C1OC1=CC=C(O)C(I)=C1 AUYYCJSJGJYCDS-LBPRGKRZSA-N 0.000 description 1
- 230000005856 abnormality Effects 0.000 description 1
- 229960000583 acetic acid Drugs 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- 238000007259 addition reaction Methods 0.000 description 1
- 229910001870 ammonium persulfate Inorganic materials 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000000110 cooling liquid Substances 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 239000012954 diazonium Substances 0.000 description 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-O diazynium Chemical compound [NH+]#N IJGRMHOSHXDMSA-UHFFFAOYSA-O 0.000 description 1
- 230000009429 distress Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 125000006575 electron-withdrawing group Chemical group 0.000 description 1
- 230000004761 fibrosis Effects 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 1
- 230000009001 hormonal pathway Effects 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 201000007270 liver cancer Diseases 0.000 description 1
- 208000014018 liver neoplasm Diseases 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 235000011056 potassium acetate Nutrition 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000002390 rotary evaporation Methods 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 235000010288 sodium nitrite Nutrition 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 239000005495 thyroid hormone Substances 0.000 description 1
- 229940036555 thyroid hormone Drugs 0.000 description 1
- 238000012795 verification Methods 0.000 description 1
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Abstract
The invention relates to the technical field of pharmaceutical intermediates, and provides a Resmetiram intermediate, a preparation method thereof and a preparation method of an intermediate III. The invention adopts the intermediate with the structure shown in the formula VI to prepare the Resmetiraom intermediate III through addition-elimination-double bond shift reaction, substitution reaction and deprotection reaction. All intermediate products of the preparation method provided by the invention are solid, so that the purification is convenient, expensive silver nitrate is not needed, the cost is low, the yield of each step is high, and the reaction time is short. In conclusion, the preparation method provided by the invention obviously reduces the difficulty, the production cost and the production period of the Resmetirom intermediate III, and is more beneficial to industrial production.
Description
Technical Field
The invention relates to the technical field of pharmaceutical intermediates, in particular to a Resmetirom intermediate, a preparation method thereof and a preparation method of an intermediate III.
Background
Resmetiram (Chinese name Resimitinol, CAS number 920509-32-6) is a drug for treating cirrhosis and fatty liver, and is now in clinical phase III studies by targeting thyroid hormone pathway to reduce liver fat. Fatty liver has become the most common sign of physical abnormalities in physical examination, and fatty liver may develop into NASH (non-alcoholic steatohepatitis), liver fibrosis, cirrhosis, and up to liver cancer without control. NASH has faced a drug-free, treatable distress over the last decades. In 2022, month 12, madrigal, the former company announced that the phase 3 trial of the THR-beta agonist MGL-3196 for NASH was successful, and phase 3 clinical data from the company showed that, with gold standard liver puncture verification, administration was performed for 52 weeks and Resmetirom reached a dual endpoint of NASH remission and improvement in fibrosis.
The molecular structure of Resmetirom is shown in formula I:
patents WO2007009913 and CN112707892 disclose the following preparation methods: under the action of silver nitrate and ammonium persulfate, the compound D and isobutyric acid generate a compound C in 67% yield, and the reaction time is longer than 24 hours; the compound C is subjected to 24h substitution reaction to prepare a compound B, and the yield is 53%; the compound III is obtained after the hydrolysis of the compound B, the yield is 50 percent, and the reaction time is more than 96 hours; the compound III is added with the compound A after diazonium reaction, double bonds are shifted, and the compound II is generated, and the yield is 56%; finally, compound II was cyclized under basic conditions to give compound I, MGL-3196, in 50% yield. The specific synthetic route is as follows:
the synthesis route has 5 steps, each step has lower yield and high cost; in addition, silver nitrate is used in the first step, so that the price is high; furthermore, compound C is an oil, which is not well purified; the above drawbacks limit the commercial production of this route.
From the above route, it can be found that the compound III is a key intermediate for synthesizing MGL-3196, and the route has the defects of difficult purification, low yield and high cost when synthesizing the compound III; therefore, there is a need to develop a method for preparing MGL-3196 intermediate III, which is easy to purify, high in yield and low in cost.
Disclosure of Invention
In view of this, the present invention provides a resepirom intermediate, a preparation method thereof, and a preparation method of intermediate III. The invention provides a Resmetirom intermediate with a structure shown in a formula VI, which is used for preparing a Resmetirom intermediate III, and the Resmetirom intermediate is easy to purify, high in yield and low in cost.
In order to achieve the above object, the present invention provides the following technical solutions:
a resepirom intermediate having the structure of formula VI:
the invention also provides a preparation method of the Resmetiraom intermediate, which comprises the following steps:
mixing a compound with a structure shown in a formula D, sodium benzene sulfinate and an organic solvent for substitution-hydrolysis reaction to obtain a compound with a structure shown in a formula VII;
and (3) mixing the compound with the structure shown in the formula VII, 3, 4-dihydro-2H-pyran, p-toluenesulfonic acid and an organic solvent for carrying out an amide protection reaction to obtain a Resmetiram intermediate with the structure shown in the formula VI.
Preferably, the molar ratio of the compound with the structure shown in the formula D to sodium benzene sulfinate is 1 (1-3);
the temperature of the substitution-hydrolysis reaction is 50-150 ℃ and the time is 1-20 h;
the organic solvent used in the substitution-hydrolysis reaction is one or more of N, N-dimethylformamide, dimethyl sulfoxide, dimethylacetamide, N-methylpyrrolidone and acetonitrile.
Preferably, the mol ratio of the compound with the structure shown in the formula VII to the 3, 4-dihydro-2H-pyran is 1 (1-4); the mol ratio of the compound with the structure shown in the formula VII to the p-toluenesulfonic acid is 1 (0.05-0.5);
the temperature of the amide protection reaction is 30-80 ℃ and the time is 1-20 h;
the organic solvent used in the amide protection reaction is one or more of tetrahydrofuran, ethyl acetate, dichloromethane, acetonitrile, acetone and 1, 4-dioxane.
The invention also provides a preparation method of the Resmetirom intermediate III, which comprises the following steps:
mixing a compound with a structure shown in a formula VI, 2-nitropropane, a first basic compound and an organic solvent to perform addition-elimination-double bond shift reaction to obtain a compound with a structure shown in a formula V;
mixing the compound with the structure shown in the formula V, 2, 6-dichloro-4-aminophenol, a second alkaline compound and an organic solvent for substitution reaction to obtain a compound with the structure shown in the formula IV;
mixing the compound with the structure shown in the formula IV with hydrochloric acid for deprotection reaction to obtain a Resmetirom intermediate III with the structural formula shown in the formula III;
preferably, the molar ratio of the compound with the structure shown in the formula VI and the 2-nitropropane is 1 (1-3);
the first alkaline compound is one or more of DBU, triethylamine, potassium carbonate, sodium carbonate, KOH and NaOH; the mol ratio of the compound with the structure shown in the formula VI to the first alkaline compound is 1 (0.2-3);
the organic solvent adopted in the addition-elimination-double bond shift reaction is one or more of N, N-dimethylformamide, dimethyl sulfoxide, dimethylacetamide, N-methylpyrrolidone, tetrahydrofuran and 1, 4-dioxane.
Preferably, the temperature of the addition-elimination-double bond shift reaction is 0-100 ℃ and the time is 0.5-10 h.
Preferably, the mol ratio of the compound with the structure shown in the formula V to the 2, 6-dichloro-4-aminophenol is 1 (1-2);
the second alkaline compound is one or more of potassium carbonate, sodium carbonate, cesium carbonate, potassium hydroxide, sodium methoxide, sodium ethoxide and potassium tert-butoxide; the mol ratio of the compound with the structure shown in the formula V to the second alkaline compound is 1 (1-3);
the organic solvent adopted in the substitution reaction is one or more of N, N-dimethylformamide, dimethyl sulfoxide, dimethylacetamide, N-methylpyrrolidone, acetonitrile and 1, 4-dioxane.
Preferably, the temperature of the substitution reaction is 40-120 ℃ and the time is 2-20 h.
Preferably, the mass fraction of the hydrochloric acid is 36-38%, and the mass ratio of the volume of the hydrochloric acid to the mass of the compound with the structure shown in the formula IV is 1-100 mL/1 g; the temperature of the deprotection reaction is 10-100 ℃ and the time is 1-10 h.
The invention provides a Resmetiram intermediate, which has a structure shown in a formula VI. Resmetirom intermediate III is prepared by using the intermediate with the structure shown in the formula VI, and the product is easy to purify, high in yield and low in cost.
The invention also provides a preparation method of the Resmetiram intermediate III, which comprises the following steps: mixing a compound with a structure shown in a formula VI, 2-nitropropane, a first basic compound and an organic solvent to perform addition-elimination-double bond shift reaction to obtain a compound with a structure shown in a formula V; mixing the compound with the structure shown in the formula V, 2, 6-dichloro-4-aminophenol, a second alkaline compound and an organic solvent for substitution reaction to obtain a compound with the structure shown in the formula IV; and mixing the compound with the structure shown in the formula IV with hydrochloric acid for deprotection reaction to obtain a Resmetirom intermediate III. In the invention, the intermediate shown in the formula VI is adopted to prepare the Resmetiram intermediate III, and in the synthetic route of the invention, all intermediate products are solid, so that the purification is convenient; the preparation method of the invention does not need to use expensive silver nitrate, has low cost and higher yield of each step. In addition, the intermediate with the structure shown in the formula VI contains phenylsulfonyl which is a strong electron-withdrawing group, so that the addition reaction activity of the compound VI for preparing the compound V is greatly enhanced, the reaction time is remarkably shortened, and meanwhile, the phenylsulfonyl is also a good leaving group, so that the substitution reaction time of the compound V for preparing the compound IV is shortened. In conclusion, the preparation method provided by the invention obviously reduces the difficulty, the production cost and the production period of the Resmetirom intermediate III, and is more beneficial to industrial production.
Drawings
FIG. 1 is a nuclear magnetic resonance hydrogen spectrum of Resmetiraom intermediate VI prepared in example 2 of the present invention;
FIG. 2 is a nuclear magnetic resonance hydrogen spectrum of Resmetiraom intermediate III prepared in example 4 of the present invention.
Detailed Description
The invention provides a Resmetiram intermediate, which has a structure shown in a formula VI:
the invention also provides a preparation method of the Resmetiraom intermediate, which comprises the following steps:
mixing a compound with a structure shown in a formula D, sodium benzene sulfinate and an organic solvent for substitution-hydrolysis reaction to obtain a compound with a structure shown in a formula VII;
and (3) mixing the compound with the structure shown in the formula VII, 3, 4-dihydro-2H-pyran, p-toluenesulfonic acid and an organic solvent for carrying out an amide protection reaction to obtain a Resmetirom intermediate with the structure shown in the formula VI.
In the present invention, the synthetic route for the resepirom intermediate of the structure shown in formula VI is as follows:
the following describes in detail the preparation of the Resmetiraom intermediate of the structure shown in formula VI.
The invention mixes the compound with the structure shown in the formula D, sodium benzene sulfinate and organic solvent for substitution-hydrolysis reaction to obtain the compound with the structure shown in the formula VII. In the present invention, the molar ratio of the compound of the structure represented by formula D to sodium benzene sulfinate is preferably 1 (1-3), more preferably 1 (1.1-2); the organic solvent used in the substitution-hydrolysis reaction is preferably one or more of N, N-Dimethylformamide (DMF), dimethylsulfoxide (DMSO), dimethylacetamide (DMAc), N-methylpyrrolidone and acetonitrile, more preferably DMF.
In the present invention, the temperature of the substitution-hydrolysis reaction is preferably 50 to 150 ℃, more preferably 80 to 120 ℃, and the time of the substitution-hydrolysis reaction is preferably 1 to 20 hours, more preferably 1.5 to 10 hours; the substitution-hydrolysis reaction is preferably carried out under nitrogen protection.
After the substitution-hydrolysis reaction is completed, the present invention preferably subjects the resulting substitution-hydrolysis reaction liquid to a post-treatment, and the method of the post-treatment preferably comprises: cooling the obtained substitution-hydrolysis reaction liquid to 50-100 ℃ (preferably 60 ℃) and then mixing with water, cooling to room temperature, pouring the obtained cooling liquid into water, stirring at room temperature and then filtering, and washing the obtained solid product with water to obtain a compound with a structure shown in a formula VII; the stirring time at room temperature is preferably 5min.
After the compound with the structure shown in the formula VII is obtained, the compound with the structure shown in the formula VII, 3, 4-dihydro-2H-pyran, p-toluenesulfonic acid and an organic solvent are mixed for amide protection reaction, so as to obtain a Resmetirom intermediate with the structure shown in the formula VI. In the present invention, the molar ratio of the compound having the structure represented by formula VII to 3, 4-dihydro-2H-pyran is preferably 1 (1-4), more preferably 1 (1.1-2); the molar ratio of the compound with the structure shown in the formula VII to the p-toluenesulfonic acid is preferably 1 (0.05-0.5), more preferably 1 (0.05-0.3); the organic solvent used in the amide protection reaction is preferably one or more of tetrahydrofuran, ethyl acetate, methylene chloride, acetonitrile, acetone and 1, 4-dioxane, more preferably tetrahydrofuran.
In the present invention, the temperature of the amide protection reaction is preferably 30 to 80 ℃, more preferably 40 to 70 ℃, and the time of the amide protection reaction is preferably 1 to 20 hours, more preferably 1.5 to 8 hours.
After the completion of the amide protection reaction, the present invention preferably subjects the resulting amide protection reaction liquid to a post-treatment, and the post-treatment method preferably includes: cooling the obtained amide protection reaction liquid to room temperature, mixing with water, adjusting the pH value of the mixed liquid to 8-10, preferably 9, stirring at room temperature, removing the organic solvent by rotary evaporation, filtering the residual liquid, washing the obtained solid product, and drying to obtain a Resmetirom intermediate with a structure shown in a formula VI; the reagent used for adjusting the pH value of the mixed solution is preferably potassium carbonate; the stirring time at room temperature is preferably 5min; the washing agent for washing the solid product is preferably a mixed solvent of ethyl acetate and heptane, and the volume ratio of the ethyl acetate to the heptane in the mixed solvent is preferably 1 (1-10), more preferably 1:2.
The invention also provides a preparation method of the Resmetirom intermediate III, which comprises the following steps:
mixing a compound with a structure shown in a formula VI, 2-nitropropane, a first basic compound and an organic solvent to perform addition-elimination-double bond shift reaction to obtain a compound with a structure shown in a formula V;
mixing the compound with the structure shown in the formula V, 2, 6-dichloro-4-aminophenol, a second alkaline compound and an organic solvent for substitution reaction to obtain a compound with the structure shown in the formula IV;
mixing the compound with the structure shown in the formula IV with hydrochloric acid for deprotection reaction to obtain a Resmetirom intermediate III with the structural formula shown in the formula III;
in the present invention, the synthetic route of the resepirom intermediate III is as follows:
the synthesis of Resmetiraom intermediate III is described in detail below.
The invention mixes the compound with the structure shown in the formula VI, the 2-nitropropane, the first alkaline compound and the organic solvent to carry out addition-elimination-double bond shift reaction, thus obtaining the compound with the structure shown in the formula V. In the present invention, the compound having the structure shown in formula VI is prepared according to the above method, and will not be described herein again; the molar ratio of the compound with the structure shown in the formula VI and the 2-nitropropane is preferably 1 (1-3), more preferably 1 (1.1-2); the first basic compound is preferably one or more of DBU, triethylamine, potassium carbonate, sodium carbonate, KOH, and NaOH, more preferably DBU; the molar ratio of the compound of the structure shown in the formula IV to the first basic compound is preferably 1 (0.2-3), more preferably 1 (0.3-2); the organic solvent used for the addition-elimination-double bond shift reaction is preferably one or more of N, N-Dimethylformamide (DMF), dimethylsulfoxide (DMSO), dimethylacetamide (DMAc), N-methylpyrrolidone (NMP), tetrahydrofuran and 1, 4-dioxane, more preferably DMSO.
In the present invention, the temperature of the addition-elimination-double bond shift reaction is preferably 0 to 100 ℃, more preferably 5 to 50 ℃, and in a specific embodiment of the present invention, the addition-elimination-double bond shift reaction is preferably performed at room temperature; the time for the addition-elimination-double bond shift reaction is preferably 0.5 to 10 hours, more preferably 0.5 to 5 hours.
After the completion of the addition-elimination-double bond shift reaction, the present invention preferably subjects the resulting addition-elimination-double bond shift reaction liquid to a post-treatment, which preferably comprises: mixing the obtained addition-elimination-double bond shift reaction solution with water, regulating the pH value of the obtained mixed solution to 3-7, preferably 5, stirring at room temperature, filtering, washing the obtained solid product, and drying to obtain a compound with a structure shown in a formula V; the reagent used for adjusting the pH value of the obtained mixed solution is preferably hydrochloric acid; the stirring time at room temperature is preferably 5min; the washing preferably comprises water washing and mixed solvent washing in sequence; the mixed solvent is preferably a mixed solvent of ethyl acetate and heptane, and the volume ratio of the ethyl acetate to the heptane is preferably 1:2.
After the compound with the structure shown in the formula V is obtained, the compound with the structure shown in the formula V, 2, 6-dichloro-4-aminophenol, a second alkaline compound and an organic solvent are mixed for substitution reaction, so that the compound with the structure shown in the formula IV is obtained. In the present invention, the molar ratio of the compound of the structure represented by the formula V to 2, 6-dichloro-4-aminophenol is preferably 1 (1-2), more preferably 1 (1-1.3); the second basic compound is preferably one or more of potassium carbonate, sodium carbonate, cesium carbonate, potassium hydroxide, sodium methoxide, sodium ethoxide and potassium tert-butoxide, more preferably potassium carbonate; the molar ratio of the compound of the structure represented by formula V to the second basic compound is preferably 1 (1-3), more preferably 1 (1-2); the organic solvent used in the substitution reaction is preferably one or more of N, N-Dimethylformamide (DMF), dimethyl sulfoxide (DMSO), dimethylacetamide (DMAc), N-methylpyrrolidone (NMP), acetonitrile and 1, 4-dioxane, and more preferably DMF.
In the present invention, the temperature of the substitution reaction is preferably 40 to 120 ℃, more preferably 50 to 100 ℃, and the time of the substitution reaction is preferably 2 to 20 hours, more preferably 2 to 10 hours.
After the substitution reaction is finished, the reaction liquid is not required to be treated, and the next reaction can be directly carried out.
After obtaining the compound with the structure shown in the formula IV, the invention mixes the compound with the structure shown in the formula IV with hydrochloric acid to carry out deprotection reaction to obtain a Resmetirom intermediate III. In the present invention, the mass fraction of the hydrochloric acid is preferably 36 to 38%, more preferably 37%, and the ratio of the volume of the hydrochloric acid to the mass of the compound having the structure represented by formula IV is preferably 1 to 100ml:1g; the temperature of the deprotection reaction is preferably 10 to 100 ℃, more preferably 30 to 70 ℃, and the time of the deprotection reaction is 1 to 10 hours, more preferably 1.5 to 5 hours. In the present invention, it is preferable that after the substitution reaction is completed, the temperature of the resulting substitution reaction solution is adjusted to the temperature of the deprotection reaction, and then hydrochloric acid is directly added thereto.
After the deprotection reaction is finished, the obtained reaction liquid is preferably subjected to post-treatment, and the post-treatment method preferably comprises the following steps: mixing the obtained deprotection reaction liquid with water, regulating the pH value of the obtained mixed liquid to 6-8, preferably 7, stirring at room temperature, filtering, washing the obtained solid product, and drying to obtain a Resmetirom intermediate III; the reagent used for adjusting the pH value of the obtained mixed solution is preferably liquid alkali; the stirring time at room temperature is preferably 5min; the washing preferably comprises water washing and mixed solvent washing in sequence; the mixed solvent is preferably a mixed solvent of ethyl acetate and heptane, and the volume ratio of the ethyl acetate to the heptane is preferably 1:2.
The following description of the embodiments of the present invention will clearly and fully describe the technical solutions of the present invention, and it is apparent that the described embodiments are only some embodiments of the present invention, not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
The methods in the following examples are conventional methods unless otherwise specified. The raw materials, reagent materials and the like used in the examples described below are commercially available products unless otherwise specified. In the following examples: the compound having the structure shown in formula D, the compound having the structure shown in formula VII, the compound having the structure shown in formula VI, the compound having the structure shown in formula V, the compound having the structure shown in formula IV and the compound having the structure shown in formula III are referred to as compound D, compound VII, compound V, compound IV and compound III, respectively.
EXAMPLE 1 preparation of Compound VII
Method 1: 14.9g of compound D (100 mmol), 19.7g (120 mmol) of sodium benzene sulfinate and 150mL of DMF are added into a reaction bottle, nitrogen protection is adopted, and the temperature is raised to 100 ℃ for reaction for 3 hours; cooling to 60 ℃, adding 10mL of water, and naturally cooling to room temperature under stirring; pouring into 600mL of water, and stirring at room temperature for 5min; filtration and washing with 50mL of water gave 22.4g of compound VII as a yellow solid in 95% yield.
Method 2: 14.9g of compound D (100 mmol), 24.6g (150 mmol) of sodium benzene sulfinate and 150mL of DMAc are added into a reaction bottle, and the mixture is heated to 90 ℃ for reaction for 5h under the protection of nitrogen; cooling to 60 ℃, adding 10mL of water, and naturally cooling to room temperature under stirring; pouring into 600mL of water, and stirring at room temperature for 5min; filtration and washing with 50mL of water gave 21.7g of compound VII as a yellow solid in 92% yield.
The nuclear magnetic data of compound VII obtained in method 1 are as follows: 1 H-NMR(400M，CDCl 3 )：8.02(2H，d)，7.90(1H，m)，7.71-7.60(4H，m)，7.07(1H，d)。
EXAMPLE 2 preparation of Compound VI
Method 1: 7.09g (30 mmol) of Compound VII, 3.78g (45 mmol) of 3, 4-dihydro-2H-pyran, 0.52g (3.0 mmol) of p-toluenesulfonic acid and 50mL of tetrahydrofuran were charged into a reaction flask, and the mixture was heated to 60℃for reaction for 5 hours; cooling to room temperature, adding 100mL of water, adjusting the pH to 9 with potassium carbonate, and stirring at room temperature for 5min; the tetrahydrofuran was spun off to precipitate a large amount of solid, which was filtered, washed with 30mL of ethyl acetate-heptane mixed solvent (volume ratio of ethyl acetate to heptane: 1:2), and dried to give 9.42g of compound VI as a pale yellow solid in 98% yield.
Method 2: 7.09g (30 mmol) of Compound VII, 5.04g (60 mmol) of 3, 4-dihydro-2H-pyran, 1.04g (6.0 mmol) of p-toluenesulfonic acid and 50mL of acetonitrile were charged into a reaction flask, and the mixture was heated to 70℃for reaction for 6 hours; cooling to room temperature, adding 100mL of water, adjusting the pH to 9 with potassium carbonate, and stirring at room temperature for 5min; the acetonitrile was swirled off, a large amount of solid was precipitated, filtered, washed with 30mL of ethyl acetate-heptane mixed solvent (volume ratio of ethyl acetate to heptane: 1:2), and dried to obtain 9.13g of pale yellow solid compound VI in 95% yield.
The nuclear magnetic data of compound VI obtained in method 1 are as follows: 1H-NMR (400M, CDCl) 3 ): 8.01 (2H, d), 7.77 (1H, d), 7.69 (1H, t), 7.59 (2H, t), 7.00 (1H, d), 5.93 (1H, d), 3.99 (1H, d), 3.69 (1H, t), 1.98 (2H, br), 1.62 (4H, br). FIG. 1 is a nuclear magnetic resonance hydrogen spectrum of compound VI.
EXAMPLE 3 preparation of Compound V
Method 1: 6.40g of Compound VI (20 mmol), 2.68g of 2-nitropropane (30 mmol), 4.56g of DBU (30 mmol) and 80mL of DMSO are added into a reaction flask and stirred at room temperature for reaction for 1h; pouring the mixture into 240mL of water, adjusting the pH to 5 with hydrochloric acid, stirring the mixture at room temperature for 5min, filtering the mixture, washing the mixture once with 40mL of water, washing the mixture with 40mL of ethyl acetate-heptane mixed solvent (the volume ratio of ethyl acetate to heptane is 1:2), and drying the mixture to obtain 7.16g of pale yellow solid compound V, wherein the yield is 99%.
Method 2: 6.40g of Compound VI (20 mmol), 3.58g of 2-nitropropane (40 mmol), 5.5g of potassium carbonate (40 mmol) and 80mL of DMF are added into a reaction flask, and the mixture is heated to 40 ℃ for reaction for 1h; pouring into 240mL of water, stirring at room temperature for 5min, filtering, washing once with 40mL of water, then washing with 40mL of ethyl acetate-heptane mixed solvent (the volume ratio of ethyl acetate to heptane is 1:2), and drying to obtain 6.88g of pale yellow solid V with the yield of 95%.
The nuclear magnetic data of compound V obtained in method 1 are as follows: 1 H-NMR(400M，DMSO-d 6 )：7.97(2H，d)，7.86(1H，m)，7.70-7.55(3H，m)，5.64(1H，dd)，3.81(1H，m)，3.51(1H，m)，3.08(1H，m)，1.62-1.43(6H，m)，1.18(6H，d)。
EXAMPLE 4 preparation of Compound III
Method 1: into the reaction flask were charged 3.62g (10 mmol) of Compound V, 2.14g of 2, 6-dichloro-4-aminophenol (12 mmol), 2.07g of potassium carbonate powder (14 mmol) and 40mL of DMF, and the mixture was stirred at 70℃for 5 hours; cooling to room temperature, adding 10mL hydrochloric acid (about 37% by mass fraction), heating to 50 ℃ and reacting for 2h; pouring into 200mL of water, regulating pH to 7 by liquid alkali, stirring at room temperature for 5min, filtering, washing once by using 20mL of water, washing by using 20mL of ethyl acetate-heptane mixed solvent (the volume ratio of ethyl acetate to heptane is 1:2), and drying to obtain 2.98g of off-white compound III, wherein the yield is 95%.
Method 2: into the reaction flask were charged 3.62g (10 mmol) of Compound V, 1.96g of 2, 6-dichloro-4-aminophenol (11 mmol), 2.12g of sodium carbonate powder (20 mmol) and 40mL of DMSO, and the mixture was stirred at 80℃for 4 hours; cooling to room temperature, adding 10mL hydrochloric acid (about 37% by mass fraction), heating to 50 ℃ and reacting for 2h; pouring into 200mL of water, regulating pH to 7 by liquid alkali, stirring at room temperature for 5min, filtering, washing once by using 20mL of water, washing by using 20mL of ethyl acetate-heptane mixed solvent (the volume ratio of ethyl acetate to heptane is 1:2), and drying to obtain 2.95g of off-white compound III, wherein the yield is 94%.
The nuclear magnetic data of compound III obtained in method 1 are as follows: 1 H-NMR(400M，DMSO-d 6 ): 12.12 (1H, s), 7.27 (1H, s), 6.67 (2H, s), 5.61 (2H, brs), 3.03 (1H, m), 1.17 (6H, d); FIG. 2 is a nuclear magnetic resonance hydrogen spectrum of compound III.
EXAMPLE 5 preparation of Compound I (Resmetirom)
Preparation of Compound II: 3.14g of Compound III (10.0 mmol), 1.72g of Compound A (11.0 mmol) and 60mL of water were added to the reaction flask, and 30mL of hydrochloric acid (37% mass fraction) was added in portions with ice water cooled to 0 to 10 ℃; maintaining the temperature at 5-10 ℃, dropwise adding a solution prepared from 6.9g of sodium nitrite (100 mmol) and 20mL of water within 30min, and then dropwise adding a solution prepared from 23.0g of sodium acetate (280 mmol) and 90mL of water within 50 min; the ice-water bath was removed, the reaction was stirred at room temperature for 2h, filtered, washed with 30mL of water and then 20mL of isopropyl etherWashing and drying gave 4.23g of Compound II as a tan solid in 88% yield. 1 H-NMR(400M，DMSO-d 6 )：δ12.26(2H，brs)，10.90(1H，s)，8.00(2H，s)，7.36(1H，s)，4.23(2H，q)，3.07(1H，m)，1.28-1.20(9H，m)。
Preparation of Compound II: 2.41g of Compound II (5.0 mmol), 0.54g of potassium acetate (5.5 mmol) and 20mL of DMF were added to the flask, and the mixture was heated to 110℃for 3 hours; cooling to 80 ℃, adding 1.0mL of glacial acetic acid, and continuously reacting for 2 hours; cooled to room temperature, 100mL of water was added, the pH was adjusted to 7 with potassium carbonate, stirred for 5min, filtered, and 20mL of acetonitrile: water = 1:2 to obtain 1.96g of yellow brown solid compound I in 90% yield. 1 H-NMR(400M，DMSO-d 6 )：13.21(1H，brs)，12.261H，brs)，7.81(2H，s)，7.46(1H，s)，3.06(1H，m)，1.18(6H，d)。
The foregoing is merely a preferred embodiment of the present invention and it should be noted that modifications and adaptations to those skilled in the art may be made without departing from the principles of the present invention, which are intended to be comprehended within the scope of the present invention.
Claims (10)
1. A resepirom intermediate having the structure of formula VI:
2. a process for the preparation of a Resmetirom intermediate according to claim 1, comprising the steps of:
mixing a compound with a structure shown in a formula D, sodium benzene sulfinate and an organic solvent for substitution-hydrolysis reaction to obtain a compound with a structure shown in a formula VII;
and (3) mixing the compound with the structure shown in the formula VII, 3, 4-dihydro-2H-pyran, p-toluenesulfonic acid and an organic solvent for carrying out an amide protection reaction to obtain a Resmetiram intermediate with the structure shown in the formula VI.
3. The preparation method according to claim 2, wherein the molar ratio of the compound of the structure represented by formula D to sodium benzene sulfinate is 1 (1-3);
the temperature of the substitution-hydrolysis reaction is 50-150 ℃ and the time is 1-20 h;
the organic solvent used in the substitution-hydrolysis reaction is one or more of N, N-dimethylformamide, dimethyl sulfoxide, dimethylacetamide, N-methylpyrrolidone and acetonitrile.
4. The preparation method according to claim 2, wherein the molar ratio of the compound of the structure represented by formula VII to 3, 4-dihydro-2H-pyran is 1 (1-4); the mol ratio of the compound with the structure shown in the formula VII to the p-toluenesulfonic acid is 1 (0.05-0.5);
the temperature of the amide protection reaction is 30-80 ℃ and the time is 1-20 h;
the organic solvent used in the amide protection reaction is one or more of tetrahydrofuran, ethyl acetate, dichloromethane, acetonitrile, acetone and 1, 4-dioxane.
5. A method for preparing a resepirom intermediate III, comprising the steps of:
mixing a compound with a structure shown in a formula VI, 2-nitropropane, a first basic compound and an organic solvent to perform addition-elimination-double bond shift reaction to obtain a compound with a structure shown in a formula V;
mixing the compound with the structure shown in the formula V, 2, 6-dichloro-4-aminophenol, a second alkaline compound and an organic solvent for substitution reaction to obtain a compound with the structure shown in the formula IV;
mixing the compound with the structure shown in the formula IV with hydrochloric acid for deprotection reaction to obtain a Resmetirom intermediate III with the structural formula shown in the formula III;
6. the process according to claim 5, wherein the molar ratio of the compound of the structure represented by formula VI to 2-nitropropane is 1 (1-3);
the first alkaline compound is one or more of DBU, triethylamine, potassium carbonate, sodium carbonate, KOH and NaOH; the mol ratio of the compound with the structure shown in the formula VI to the first alkaline compound is 1 (0.2-3);
the organic solvent adopted in the addition-elimination-double bond shift reaction is one or more of N, N-dimethylformamide, dimethyl sulfoxide, dimethylacetamide, N-methylpyrrolidone, tetrahydrofuran and 1, 4-dioxane.
7. The process according to claim 5, wherein the temperature of the addition-elimination-double bond shift reaction is 0 to 100℃for 0.5 to 10 hours.
8. The preparation method according to claim 5, wherein the molar ratio of the compound of the structure represented by formula V to 2, 6-dichloro-4-aminophenol is 1 (1-2);
the second alkaline compound is one or more of potassium carbonate, sodium carbonate, cesium carbonate, potassium hydroxide, sodium methoxide, sodium ethoxide and potassium tert-butoxide; the mol ratio of the compound with the structure shown in the formula V to the second alkaline compound is 1 (1-3);
the organic solvent adopted in the substitution reaction is one or more of N, N-dimethylformamide, dimethyl sulfoxide, dimethylacetamide, N-methylpyrrolidone, acetonitrile and 1, 4-dioxane.
9. The method according to claim 5, wherein the temperature of the substitution reaction is 40 to 120℃for 2 to 20 hours.
10. The preparation method according to claim 5, wherein the mass fraction of the hydrochloric acid is 36-38%, and the ratio of the volume of the hydrochloric acid to the mass of the compound of the structure shown in formula IV is 1-100 ml:1g; the temperature of the deprotection reaction is 10-100 ℃ and the time is 1-10 h.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202311118581.4A CN117164568A (en) | 2023-09-01 | 2023-09-01 | Resmetirom intermediate and preparation method thereof as well as preparation method of intermediate III |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202311118581.4A CN117164568A (en) | 2023-09-01 | 2023-09-01 | Resmetirom intermediate and preparation method thereof as well as preparation method of intermediate III |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN117164568A true CN117164568A (en) | 2023-12-05 |
Family
ID=88931247
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202311118581.4A Pending CN117164568A (en) | 2023-09-01 | 2023-09-01 | Resmetirom intermediate and preparation method thereof as well as preparation method of intermediate III |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN117164568A (en) |
-
2023
- 2023-09-01 CN CN202311118581.4A patent/CN117164568A/en active Pending
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN111423452B (en) | Intermediate of Rayleigh Lu Geli and preparation method and application thereof | |
| CN112851646B (en) | Preparation method of tergolian prazan | |
| US20230257392A1 (en) | Intermediate for synthesizing camptothecin derivative, preparation method therefor, and use thereof | |
| CN108467396A (en) | A kind of preparation method of Ganciclovir | |
| JP2023524626A (en) | Method for synthesizing roxadustat and intermediates thereof and intermediates thereof | |
| CN114315823B (en) | Intermediate of berberine hydrochloride and analogues thereof and preparation method thereof | |
| CN102351778A (en) | Preparation method of arbidol hydrochloride | |
| WO2022111448A1 (en) | Method for preparing btk degrading agent | |
| CN108191858B (en) | A kind of intermediate preparing pyrroloquinoline quinone and preparation method | |
| EP3527556B1 (en) | Method for preparing deuterated imidazole diketone compound | |
| CN117164568A (en) | Resmetirom intermediate and preparation method thereof as well as preparation method of intermediate III | |
| CN111377864A (en) | Lovatinib impurity and preparation method and application thereof | |
| WO2020020190A1 (en) | Method for synthesizing quinoline derivative | |
| CN113045475A (en) | Preparation method of 5-bromo-7-methylindole | |
| CN110407702A (en) | A kind of preparation method of eltrombopag olamine key intermediate 3 '-amino -2 '-xenol -3- carboxylic acid | |
| CN110577542A (en) | Preparation method of sitagliptin | |
| CN114524802B (en) | Synthesis method of quinoline compound | |
| JPH11116576A (en) | Production of 2-choloro-benzimidazole derivative | |
| CN111333528B (en) | Synthesis method of multi-configuration O-phenyl-serine compound | |
| CN117603149A (en) | Resmetirom intermediate and preparation method thereof as well as preparation method of key intermediate III | |
| JP2003506312A (en) | Meta-nitrophenol derivative and method for producing the same | |
| CN118271248A (en) | Raffinterol intermediate and preparation method thereof, and preparation method of Raffinterol | |
| CN115557885A (en) | Preparation method of sodium picosulfate | |
| JPH051023A (en) | Production of alkanesulfonanilide derivative | |
| US5387716A (en) | N4-substituted 1-alkoxy-2-acylamino-4-aminobenzenes, process for their preparation and their use |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination |