CN113999107A - Method for efficiently preparing 3-alkyl-2-hydroxybenzoic acid - Google Patents
Method for efficiently preparing 3-alkyl-2-hydroxybenzoic acid Download PDFInfo
- Publication number
- CN113999107A CN113999107A CN202111285423.9A CN202111285423A CN113999107A CN 113999107 A CN113999107 A CN 113999107A CN 202111285423 A CN202111285423 A CN 202111285423A CN 113999107 A CN113999107 A CN 113999107A
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- China
- Prior art keywords
- acid
- compound
- alkyl
- hydroxybenzoic acid
- 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
- 229960004889 salicylic acid Drugs 0.000 title claims abstract description 7
- 238000000034 method Methods 0.000 title claims description 10
- 238000002360 preparation method Methods 0.000 claims abstract description 13
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 claims description 10
- 150000001875 compounds Chemical class 0.000 claims description 10
- 239000002253 acid Substances 0.000 claims description 9
- 239000002841 Lewis acid Substances 0.000 claims description 8
- 150000007517 lewis acids Chemical class 0.000 claims description 8
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims description 7
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 6
- 229910002092 carbon dioxide Inorganic materials 0.000 claims description 6
- 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 6
- 239000001569 carbon dioxide Substances 0.000 claims description 5
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 5
- 229910007932 ZrCl4 Inorganic materials 0.000 claims description 4
- 230000008569 process Effects 0.000 claims description 4
- DUNKXUFBGCUVQW-UHFFFAOYSA-J zirconium tetrachloride Chemical compound Cl[Zr](Cl)(Cl)Cl DUNKXUFBGCUVQW-UHFFFAOYSA-J 0.000 claims description 4
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 claims description 3
- 229910003074 TiCl4 Inorganic materials 0.000 claims description 3
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 claims description 3
- 229940092714 benzenesulfonic acid Drugs 0.000 claims description 3
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 claims description 3
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 3
- 125000006239 protecting group Chemical group 0.000 claims description 3
- 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 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 claims description 2
- KRHYYFGTRYWZRS-UHFFFAOYSA-M Fluoride anion Chemical compound [F-] KRHYYFGTRYWZRS-UHFFFAOYSA-M 0.000 claims description 2
- BLRPTPMANUNPDV-UHFFFAOYSA-N Silane Chemical compound [SiH4] BLRPTPMANUNPDV-UHFFFAOYSA-N 0.000 claims description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 238000006555 catalytic reaction Methods 0.000 claims description 2
- 125000001033 ether group Chemical group 0.000 claims description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- 230000003301 hydrolyzing effect Effects 0.000 claims description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 2
- 150000002642 lithium compounds Chemical class 0.000 claims description 2
- 229910003002 lithium salt Inorganic materials 0.000 claims description 2
- 159000000002 lithium salts Chemical class 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 claims 2
- 238000004519 manufacturing process Methods 0.000 claims 2
- 229910000077 silane Inorganic materials 0.000 claims 1
- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 claims 1
- 238000006243 chemical reaction Methods 0.000 abstract description 10
- 229940079593 drug Drugs 0.000 abstract description 10
- 239000003814 drug Substances 0.000 abstract description 10
- ZTGYRAPTDJTYGC-UHFFFAOYSA-N 3-ethyl-2-hydroxybenzoic acid Chemical compound CCC1=CC=CC(C(O)=O)=C1O ZTGYRAPTDJTYGC-UHFFFAOYSA-N 0.000 abstract description 5
- 238000007254 oxidation reaction Methods 0.000 abstract description 5
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- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 9
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- YQNQNVDNTFHQSW-UHFFFAOYSA-N acetic acid [2-[[(5-nitro-2-thiazolyl)amino]-oxomethyl]phenyl] ester Chemical compound CC(=O)OC1=CC=CC=C1C(=O)NC1=NC=C([N+]([O-])=O)S1 YQNQNVDNTFHQSW-UHFFFAOYSA-N 0.000 description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 208000002672 hepatitis B Diseases 0.000 description 6
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 5
- 229960002480 nitazoxanide Drugs 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- 230000000840 anti-viral effect Effects 0.000 description 4
- 208000015181 infectious disease Diseases 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- NDVLTYZPCACLMA-UHFFFAOYSA-N silver oxide Chemical compound [O-2].[Ag+].[Ag+] NDVLTYZPCACLMA-UHFFFAOYSA-N 0.000 description 4
- SQGYOTSLMSWVJD-UHFFFAOYSA-N silver(1+) nitrate Chemical compound [Ag+].[O-]N(=O)=O SQGYOTSLMSWVJD-UHFFFAOYSA-N 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- XGAYQDWZIPRBPF-UHFFFAOYSA-N 2-hydroxy-3-propan-2-ylbenzoic acid Chemical compound CC(C)C1=CC=CC(C(O)=O)=C1O XGAYQDWZIPRBPF-UHFFFAOYSA-N 0.000 description 3
- CRBJBYGJVIBWIY-UHFFFAOYSA-N 2-isopropylphenol Chemical compound CC(C)C1=CC=CC=C1O CRBJBYGJVIBWIY-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- KWYHDKDOAIKMQN-UHFFFAOYSA-N N,N,N',N'-tetramethylethylenediamine Chemical compound CN(C)CCN(C)C KWYHDKDOAIKMQN-UHFFFAOYSA-N 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
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- IXQGCWUGDFDQMF-UHFFFAOYSA-N 2-Ethylphenol Chemical compound CCC1=CC=CC=C1O IXQGCWUGDFDQMF-UHFFFAOYSA-N 0.000 description 2
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- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 2
- 229930040373 Paraformaldehyde Natural products 0.000 description 2
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- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 2
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- 108090000623 proteins and genes Proteins 0.000 description 2
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- 229910001961 silver nitrate Inorganic materials 0.000 description 2
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- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
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- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- AKLBERUGKZNEJY-RTEPGWBGSA-N (5s,8s,10ar)-3-[3-[[(5s,8s,10ar)-8-(benzhydrylcarbamoyl)-5-[[(2s)-2-(methylamino)propanoyl]amino]-6-oxo-1,2,4,5,8,9,10,10a-octahydropyrrolo[1,2-a][1,5]diazocin-3-yl]sulfonyl]phenyl]sulfonyl-n-benzhydryl-5-[[(2s)-2-(methylamino)propanoyl]amino]-6-oxo-1,2,4 Chemical compound O=C([C@@H]1CC[C@@H]2CCN(C[C@@H](C(N21)=O)NC(=O)[C@H](C)NC)S(=O)(=O)C=1C=C(C=CC=1)S(=O)(=O)N1C[C@@H](C(=O)N2[C@@H](CC[C@@H]2CC1)C(=O)NC(C=1C=CC=CC=1)C=1C=CC=CC=1)NC(=O)[C@H](C)NC)NC(C=1C=CC=CC=1)C1=CC=CC=C1 AKLBERUGKZNEJY-RTEPGWBGSA-N 0.000 description 1
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- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical class [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- UJTOVSZPBVTOMC-QKZHPOIUSA-N Tizoxanide glucuronide Chemical compound O1[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1OC1=CC=CC=C1C(=O)NC1=NC=C([N+]([O-])=O)S1 UJTOVSZPBVTOMC-QKZHPOIUSA-N 0.000 description 1
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- AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/347—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups
- C07C51/367—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by introduction of functional groups containing oxygen only in singly bound form
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
- C07D309/16—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D309/28—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D309/30—Oxygen atoms, e.g. delta-lactones
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
- C07F7/1872—Preparation; Treatments not provided for in C07F7/20
- C07F7/188—Preparation; Treatments not provided for in C07F7/20 by reactions involving the formation of Si-O linkages
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
- C07F7/1872—Preparation; Treatments not provided for in C07F7/20
- C07F7/1892—Preparation; Treatments not provided for in C07F7/20 by reactions not provided for in C07F7/1876 - C07F7/1888
-
- 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
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Abstract
The invention discloses an industrial preparation method of a drug intermediate, relates to a preparation method of 3-alkyl-2-hydroxybenzoic acid, and belongs to the field of pharmaceutical chemistry. Taking 3-ethyl-2-hydroxybenzoic acid as an example, the synthetic route is as follows:
Description
Technical Field
The invention relates to a large-scale preparation method of a drug intermediate, relates to a preparation method of 3-alkyl-2-hydroxybenzoic acid, and belongs to the field of pharmaceutical chemistry.
Background
Chronic Hepatitis B Virus (HBV) infection is a common cause of severe liver disease worldwide. The number of newly-infected people of hepatitis B virus in China is up to more than 100 ten thousand every year, and the total number of infected people is 9000 ten thousand. According to the World Health Organization (WHO), there are approximately 2.57 billion HBV infected patients worldwide. Approximately more than 65 million people die each year from HBV infection-related end-stage liver disease, including liver failure, cirrhosis, and hepatocellular carcinoma (HCC). Currently, vaccines, Nucleoside (NA) or Nucleotide (NUC) based drugs are effective in reducing the rate of new infections and can slow the progression of liver disease in HBV patients who adhere to long-term viral suppression therapy. The negative conversion of hepatitis B surface antigen (HBsAg) is related to liver function improvement, histopathological improvement and long-term prognosis improvement, and is an ideal treatment target recommended by the latest domestic and overseas chronic hepatitis B control guidelines at present, namely a target for functional treatment or clinical treatment of hepatitis B. However, the use of direct antiviral Drugs (DAAs) [ such as nucleoside (acid) analogs (NA) ] or immunomodulators [ such as pegylated interferon alpha (PEG-IFN) ] alone has limited efficacy in achieving clinical healing. In theory, NA and PEG-IFN exert different antiviral effects against HBV, and a reasonable combination can produce synergistic and complementary effects, but still the cure rate is low. Some drugs with new mechanisms of action are now beginning to enter clinical trials, such as immune checkpoint Inhibitors (anti-PD-1 or anti-CTLA-4 therapy), capsid assembly Inhibitors (AT-130, NVR-3778, JNJ6379, etc.), RNAi therapies (JNJ3989 or ARO-HBV) and Apoptosis protein Inhibitors (IAP, Inhibitors of Apoptosis Proteins) Inhibitors (such as APG-1387), etc. (Fanning et al, Nature Reviews drug discovery volume 18, pages 827-844 (2019)). None of these achieve the goal of curative hepatitis b. Therefore, there is a need to find more effective drugs for treating hepatitis B, especially drugs that can inhibit hepatitis B surface antigen, and improve the functional cure rate.
The novel coronavirus (COVID-19) has the advantages that the worldwide infection number reaches 1.17 hundred million and the death number exceeds 260 ten thousand from the global outbreak at the end of 2019 to 2021, namely at the end of 3 months and 17 days, and no obvious end sign exists. Although several vaccines have been granted emergency access, no effective drug has been officially approved for marketing. The discovery of therapeutic drugs with definite curative effects is urgently needed, and the health risk caused by the current COVID-19 is solved.
In recent years, it has been found that nitazoxanide has a broad-spectrum Antiviral effect (J.genetic Engineering and biotechnology 2020,18,1) and has a significant inhibitory effect on various proteins of hepatitis B virus, including HBsAg, HBeAg, HBcAg, HBV R.I., HBV RNA, cccDNA and variant strains of HBV (Antiviral Res.2008,77, 56). Nitazoxanide can also significantly inhibit the replication of new corona virus (j.infect.dev.ctries.2020,14,982). Nitazoxanide (Nitazoxanide, 1) was discovered in the limark Laboratories (Remark Laboratories) in 1976 and was originally used for the treatment of taenia infections. The compound is firstly marketed in Mexico as an antiparasitic drug, and the trade name in English is: daxon and Colufase; the product is sold in Australia, New Zealand and other countries with the trade name of CryptazTM; nitazoxanide is approved in the united states at 11 months 2002 as a therapeutic for childhood diarrhea caused by cryptosporidium, giardia lamblia, and marketed under the trade name alias.
It has been reported that the active ingredient 2 of compound 1 is very susceptible to glycosylation in vivo to produce compound 3(TZG, Tizoxanide Glucuronide) having no biological activity, so that the drug concentration in plasma sometimes hardly reaches an effective therapeutic concentration, which affects the clinical therapeutic effect.
The inventor hopes to increase the steric hindrance effect of the ortho position of the hydroxyl group and reduce the glycosylation of the hydroxyl group by introducing a substituent to the ortho position of the hydroxyl group, so as to improve the efficacy and exposure of the drug.
The substituted derivative 4 of the compound 1 has obvious advantages in antiviral and drug exposure compared with the compound 1. The inventor has applied for an invention patent (Chinese patent application No. 202110550766.7).
The synthetic intermediate 3-ethyl-2-hydroxybenzoic acid (11) of compound 4 was not reported as a direct preparation method. However, a synthesis method of a similar compound 3-isopropyl-2-hydroxybenzoic acid (8) is reported as follows (WO 2009/140275A 1):
the 2-isopropyl phenol (6) is firstly formalized to obtain a compound (7) and then oxidized to be 3-isopropyl-2-hydroxybenzoic acid (8), and because the phenolic hydroxyl group is easy to oxidize, the oxidant can only be selected from mild silver oxide.
According to the literature method, the inventor applied the similar method to synthesize 3-ethyl-2-hydroxybenzoic acid (11) in the original invention application, compound 9 was heated with paraformaldehyde in tetrahydrofuran in the presence of anhydrous magnesium chloride and triethylamine to obtain compound 10, followed by oxidation with silver nitrate in ethanol to obtain compound 11, the total yield of both parts was 33%.
The preparation method has obvious defects of low total reaction yield, expensive price of the used oxidant and silver oxide and unsuitability for large-scale industrial production of oxidation reaction. Therefore, there is a need to find more efficient synthetic methods suitable for large-scale production.
Disclosure of Invention
The invention aims to provide a method for preparing 3-ethyl-2-hydroxybenzoic acid with high efficiency and suitability for large-scale industrialization. The synthetic route is as follows:
the compound 9 reacts with 3, 4-dihydro-2H-pyran under the catalysis of acid or Lewis acid to quantitatively generate an intermediate 12. Compound 12 is treated with butyl lithium in the presence of N, N' -Tetramethylethylenediamine (TMEDA) to give a lithiated intermediate, which is then quenched with carbon dioxide gas to give compound 11. The total yield was 54%.
The acid or Lewis acid used for ether protection is selected from, but not limited to, sulfonic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, ZrCl4,ZnCl4,TiCl4And the like.
The general procedure for the preparation of 3-alkyl-2-hydroxybenzoic acids was as follows:
a. the compound II is catalyzed by acid or Lewis acid to protect phenolic hydroxyl by the following reaction:
pg can be selected from:
wherein, R, R1-R6Are respectively selected from C1-10Preferably methyl, ethyl, isopropyl, butyl, isobutyl, tert-butyl.
The acid or Lewis acid used for ether protection is selected from, but not limited to, sulfonic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, ZrCl4,ZnCl4,TiCl4And the like.
b. Reacting the compound III with butyl lithium to obtain a lithium compound IV:
r, R therein1-R6Is as defined above.
c. Reacting the compound IV with carbon dioxide to obtain lithium salt V:
d. hydrolyzing the compound V and removing the protecting group by a conventional method to obtain a target product I:
ether protecting groups are preferentially hydrolyzed with acid or lewis acid catalysis, and silane protecting groups are preferentially hydrolyzed with fluoride.
The invention has the advantages that: the reaction route of the invention does not use expensive oxidant, not only avoids oxidation reaction, but also obviously improves reaction yield, the yield reaches more than 54 percent, and the invention is very beneficial to industrial production.
Detailed Description
The following describes in detail embodiments of the present invention. It should be understood that the embodiments described herein are illustrative only and are not limiting. Comparative example 1 Oxidation preparation of Compound 11
Compound 9(10g, 81.86mmol), paraformaldehyde (4.9g, 163.7mmol), anhydrous magnesium chloride (10.1g, 106.4mmol), triethylamine (14.8mL, 106.42mmol) were added to THF (100mL), the mixture was refluxed overnight under nitrogen protection, cooled, 1N HCl was added to adjust pH to 2-3, ethyl acetate (200mL) was added for extraction, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated to dryness, and the residue was purified by column chromatography, washed with ethyl acetate: elution with petroleum ether-20: 1 gave a colorless oil (4.3g, 35%).1H NMR(400MHz,CDCl3)δ11.31(d,J＝0.4Hz,1H),9.89 (s,1H),7.42(dd,J＝2.5,1.1Hz,1H),7.40(dd,J＝3.0,1.1Hz,1H), 6.96(t,J＝7.6Hz,1H),2.70(q,J＝7.5Hz,2H),1.23(t,J＝7.5Hz, 3H)。
Dissolving the compound 10(4.3g, 28.6mmol) in ethanol (50mL), adding silver nitrate (7.3g, 42.9mmol), sodium hydroxide (4.6g, 114.5mmol), refluxing overnight, cooling, adding 1N HCl to adjust pH to 2-3, filtering, evaporating ethanol, extracting the residue with ethyl acetate (200mL), washing the organic phase with saturated common salt water, drying with anhydrous sodium sulfate, filtering, evaporating solvent to obtain a yellow solid product (4.5g, 95%). The total yield of the two steps is 33%.
EXAMPLE 1 preparation of Compound 11 by carbon dioxide Process
1. Preparation of Compound 12
3, 4-dihydro-2H-pyran (16.82g,0.20mol) was added at room temperature to a solution containing 2-ethylphenol (12.2g, 0.10mol) and ZrCl4(0.5mmol) in dichloromethane (5mL) and the reaction mixture stirred for an additional 3 hours, after completion of the reaction, water (5mL) was added and the compound was reacted with tolueneTert-butyl ether (20mL) was extracted and the organic solution was washed with saturated sodium bicarbonate, brine, dried over anhydrous sodium sulfate, filtered and the solvent was evaporated to give the product (29.5g, 96%).1H NMR(400MHz，CDCl3，ppm):δ7.18-7.09(m,3H),6.93(td, J＝7.2,1.4Hz,1H),5.44(t,J＝3.1Hz,1H),3.95-3.89(m,1H),3.65-3.60 (m,1H),2.70(q,J＝7.5Hz,2H),2.08-1.99(m,1H),1.91-1.88(m,2H), 1.73-1.61(m,3H),1.24(t,J＝7.5Hz,3H)。
2. Preparation of compound 11 by carbon dioxide process
THF (3000mL) was added to the reaction flask. To the reaction mixture was added mixture 12(200g, 0.97 mol) and TMEDA (136.0g, 1.16 mol). Under the protection of nitrogen, cooling to-30-20 ℃, slowly dripping n-BuLi (464mL, 1.16mol, 2.5M) into the reaction mixture, stirring for 1.5 hours at-30-20 ℃ after dripping, heating to-15-5 ℃, continuing stirring for 1 +/-0.5 hours, and introducing CO2Controlling the temperature of the gas to be-20 to-10 ℃, and stirring for 1.5 hours. And (3) slowly adding 3N HCl (2000mL) at the temperature of-10-0 ℃, and after the 3N HCl is added, heating to 20-30 ℃ and stirring for 30 minutes. The reaction solution is decompressed and concentrated to remove THF under the condition of 50 ℃ and vacuum degree less than or equal to-0.08 Mpa. MTBE (2000mL) was added to the concentrate for extraction, and the organic phase was extracted with 3N HCl (1000mL) and H, respectively2O (1000mL) wash. Concentrating the organic phase at 50 deg.C under vacuum degree of less than or equal to-0.08 Mpa under reduced pressure for 2-3 times, adding n-heptane (800mL), and further concentrating to 2-3 times. And adding n-heptane (400mL) into the concentrated solution, cooling to-10-0 ℃, and stirring for 30 minutes. Filtration and the filter cake rinsed with n-heptane (200mL, 0-10 ℃ C.). The filter cake was dried at 50 ℃ under a vacuum of-0.08 MPa or less for 6 hours to give a white solid product (87.7g, 54.43%).1H NMR(400MHz, CDCl3)δ11.52(s,1H),10.63(s,1H),7.80(dd,J＝8.0,1.7Hz,1H), 7.41(dd,J＝7.3,1.0Hz,1H),6.88(t,J＝7.7Hz,1H),2.71(q,J＝ 7.5Hz,2H),1.24(t,J＝7.5Hz,3H).m/z(ESI)[M-H]-＝165.1。
Claims (4)
1. A process for the preparation of 3-alkyl-2-hydroxybenzoic acids of the general formula I below, characterized in that it is carried out by:
wherein: r is selected from C1-10Alkyl groups of (a);
a. and (3) under the catalysis of acid or Lewis acid, protecting the hydroxyl group of the compound II to obtain a compound III:
pg is selected from:
wherein R is1-R6Are respectively selected from C1-10Alkyl groups of (a);
the acid or Lewis acid is selected from sulfonic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, ZrCl4,ZnCl4,TiCl4；
b. Reacting the compound III with butyl lithium to obtain a lithium compound IV:
c. reacting the compound IV with carbon dioxide to obtain lithium salt V:
d. hydrolyzing the compound V, and removing a protecting group to obtain a target product I:
2. the process for preparing 3-alkyl-2-hydroxybenzoic acid as claimed in claim 1, wherein R is selected from the group consisting of methyl, ethyl, isopropyl, butyl, isobutyl, and tert-butyl.
3. The process for preparing 3-alkyl-2-hydroxybenzoic acid according to claim 1 or 2, wherein the ether protecting group of step (d) is hydrolyzed with an acid or a lewis acid.
4. The process for the preparation of 3-alkyl-2-hydroxybenzoic acid according to claim 1 or 2, wherein the silane-based protecting group of step (d) is hydrolyzed with fluoride.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004078693A1 (en) * | 2003-03-04 | 2004-09-16 | Kabushiki Kaisha Ueno Seiyaku Oyo Kenkyujo | Process for production of hydroxybenzoic acids |
| US20120264668A1 (en) * | 2009-11-24 | 2012-10-18 | Henkel Ag & Co. Kgaa | Detergents or cleaning agents containing a bleach-enhancing transition metal complex which is optionally produced in situ |
| CN107531601A (en) * | 2015-04-20 | 2018-01-02 | 尤尼威蒂恩技术有限责任公司 | Bridging biaryl perfume base ligand and transistion metal compound prepared therefrom |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004078693A1 (en) * | 2003-03-04 | 2004-09-16 | Kabushiki Kaisha Ueno Seiyaku Oyo Kenkyujo | Process for production of hydroxybenzoic acids |
| US20120264668A1 (en) * | 2009-11-24 | 2012-10-18 | Henkel Ag & Co. Kgaa | Detergents or cleaning agents containing a bleach-enhancing transition metal complex which is optionally produced in situ |
| CN107531601A (en) * | 2015-04-20 | 2018-01-02 | 尤尼威蒂恩技术有限责任公司 | Bridging biaryl perfume base ligand and transistion metal compound prepared therefrom |
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| HARRIS, THOMAS D. ET AL.: "Substituent modification in tri-o-thymotide and its effects on host geometry and guest enclathration. 1. Synthesis", 《TETRAHEDRON》, vol. 43, no. 7, pages 1519 - 1540, XP026607957, DOI: 10.1016/S0040-4020(01)90268-6 * |
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