CN107353275B - Synthesis method of xanthene-9-formic acid - Google Patents
Synthesis method of xanthene-9-formic acid Download PDFInfo
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- CN107353275B CN107353275B CN201710438709.3A CN201710438709A CN107353275B CN 107353275 B CN107353275 B CN 107353275B CN 201710438709 A CN201710438709 A CN 201710438709A CN 107353275 B CN107353275 B CN 107353275B
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- carboxylic acid
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- VSBFNCXKYIEYIS-UHFFFAOYSA-N Xanthene-9-carboxylic acid Chemical compound C1=CC=C2C(C(=O)O)C3=CC=CC=C3OC2=C1 VSBFNCXKYIEYIS-UHFFFAOYSA-N 0.000 title claims abstract description 33
- 238000001308 synthesis method Methods 0.000 title description 3
- 238000000034 method Methods 0.000 claims abstract description 26
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 17
- ATOQLGNDBZUHKM-UHFFFAOYSA-N 9h-xanthene-9-carbonitrile Chemical compound C1=CC=C2C(C#N)C3=CC=CC=C3OC2=C1 ATOQLGNDBZUHKM-UHFFFAOYSA-N 0.000 claims abstract description 12
- QDLAGTHXVHQKRE-UHFFFAOYSA-N lichenxanthone Natural products COC1=CC(O)=C2C(=O)C3=C(C)C=C(OC)C=C3OC2=C1 QDLAGTHXVHQKRE-UHFFFAOYSA-N 0.000 claims abstract description 12
- 230000002194 synthesizing effect Effects 0.000 claims abstract description 12
- GJCOSYZMQJWQCA-UHFFFAOYSA-N 9H-xanthene Chemical compound C1=CC=C2CC3=CC=CC=C3OC2=C1 GJCOSYZMQJWQCA-UHFFFAOYSA-N 0.000 claims abstract description 10
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 9
- 238000005658 halogenation reaction Methods 0.000 claims abstract description 7
- 239000003960 organic solvent Substances 0.000 claims abstract description 5
- 150000003732 xanthenes Chemical class 0.000 claims abstract description 5
- 239000003054 catalyst Substances 0.000 claims abstract description 3
- 239000012535 impurity Substances 0.000 claims abstract description 3
- 230000026030 halogenation Effects 0.000 claims abstract 2
- 238000006243 chemical reaction Methods 0.000 claims description 33
- JNELGWHKGNBSMD-UHFFFAOYSA-N xanthone Chemical compound C1=CC=C2C(=O)C3=CC=CC=C3OC2=C1 JNELGWHKGNBSMD-UHFFFAOYSA-N 0.000 claims description 18
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 14
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 12
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 11
- 238000001914 filtration Methods 0.000 claims description 10
- 238000006722 reduction reaction Methods 0.000 claims description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 9
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- 239000002904 solvent Substances 0.000 claims description 6
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 6
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Substances [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 claims description 5
- 230000035484 reaction time Effects 0.000 claims description 5
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims description 4
- 230000002140 halogenating effect Effects 0.000 claims description 4
- JHJLBTNAGRQEKS-UHFFFAOYSA-M sodium bromide Inorganic materials [Na+].[Br-] JHJLBTNAGRQEKS-UHFFFAOYSA-M 0.000 claims description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 3
- MNZMECMQTYGSOI-UHFFFAOYSA-N acetic acid;hydron;bromide Chemical compound Br.CC(O)=O MNZMECMQTYGSOI-UHFFFAOYSA-N 0.000 claims description 3
- 239000003153 chemical reaction reagent Substances 0.000 claims description 3
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 claims description 3
- 229940011051 isopropyl acetate Drugs 0.000 claims description 3
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 claims description 3
- XNWFRZJHXBZDAG-UHFFFAOYSA-N 2-METHOXYETHANOL Chemical compound COCCO XNWFRZJHXBZDAG-UHFFFAOYSA-N 0.000 claims description 2
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 claims description 2
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 2
- MHABMANUFPZXEB-UHFFFAOYSA-N O-demethyl-aloesaponarin I Natural products O=C1C2=CC=CC(O)=C2C(=O)C2=C1C=C(O)C(C(O)=O)=C2C MHABMANUFPZXEB-UHFFFAOYSA-N 0.000 claims description 2
- 229910020667 PBr3 Inorganic materials 0.000 claims description 2
- 239000003638 chemical reducing agent Substances 0.000 claims description 2
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 claims description 2
- 229910000041 hydrogen chloride Inorganic materials 0.000 claims description 2
- 230000003472 neutralizing effect Effects 0.000 claims description 2
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 claims description 2
- 238000010189 synthetic method Methods 0.000 claims description 2
- 239000002253 acid Substances 0.000 claims 1
- 239000000203 mixture Substances 0.000 claims 1
- 238000003786 synthesis reaction Methods 0.000 abstract description 10
- 239000002994 raw material Substances 0.000 abstract description 9
- 238000006386 neutralization reaction Methods 0.000 abstract description 6
- 239000007864 aqueous solution Substances 0.000 abstract description 5
- -1 xanthene ketone Chemical class 0.000 abstract description 4
- 238000009776 industrial production Methods 0.000 abstract description 3
- 238000007670 refining Methods 0.000 abstract description 3
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 abstract description 2
- 239000003513 alkali Substances 0.000 abstract description 2
- 230000007062 hydrolysis Effects 0.000 abstract description 2
- 238000000638 solvent extraction Methods 0.000 abstract 1
- 239000007787 solid Substances 0.000 description 16
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- 238000010438 heat treatment Methods 0.000 description 10
- 230000015572 biosynthetic process Effects 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- 238000001816 cooling Methods 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- RQMNNDHEGSDJRX-UHFFFAOYSA-N 9-chloro-9h-xanthene Chemical compound C1=CC=C2C(Cl)C3=CC=CC=C3OC2=C1 RQMNNDHEGSDJRX-UHFFFAOYSA-N 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 4
- 238000012544 monitoring process Methods 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 3
- 229960000583 acetic acid Drugs 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 239000005457 ice water Substances 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 238000001291 vacuum drying Methods 0.000 description 3
- 239000011701 zinc Substances 0.000 description 3
- 229910021595 Copper(I) iodide Inorganic materials 0.000 description 2
- 208000008469 Peptic Ulcer Diseases 0.000 description 2
- 239000004280 Sodium formate Substances 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- FNXLCIKXHOPCKH-UHFFFAOYSA-N bromamine Chemical compound BrN FNXLCIKXHOPCKH-UHFFFAOYSA-N 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- LELOWRISYMNNSU-UHFFFAOYSA-N hydrogen cyanide Chemical compound N#C LELOWRISYMNNSU-UHFFFAOYSA-N 0.000 description 2
- 229910052744 lithium Inorganic materials 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- 208000011906 peptic ulcer disease Diseases 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- MNWBNISUBARLIT-UHFFFAOYSA-N sodium cyanide Chemical compound [Na+].N#[C-] MNWBNISUBARLIT-UHFFFAOYSA-N 0.000 description 2
- JFRMYMMIJXLMBB-UHFFFAOYSA-N xanthydrol Chemical compound C1=CC=C2C(O)C3=CC=CC=C3OC2=C1 JFRMYMMIJXLMBB-UHFFFAOYSA-N 0.000 description 2
- DSFGXPJYDCSWTA-UHFFFAOYSA-N 7-[2-hydroxy-3-[2-hydroxyethyl(methyl)amino]propyl]-1,3-dimethylpurine-2,6-dione Chemical compound CN1C(=O)N(C)C(=O)C2=C1N=CN2CC(O)CN(CCO)C DSFGXPJYDCSWTA-UHFFFAOYSA-N 0.000 description 1
- SVTRGKQOMSDSRW-UHFFFAOYSA-N 9H-xanthene-9-carboxylic acid Chemical compound OC(=O)C1c2ccccc2Oc2ccccc12.OC(=O)C1c2ccccc2Oc2ccccc12 SVTRGKQOMSDSRW-UHFFFAOYSA-N 0.000 description 1
- TTWQJTZYBXHGKQ-UHFFFAOYSA-N 9h-xanthene-1-carboxylic acid Chemical compound O1C2=CC=CC=C2CC2=C1C=CC=C2C(=O)O TTWQJTZYBXHGKQ-UHFFFAOYSA-N 0.000 description 1
- 208000007882 Gastritis Diseases 0.000 description 1
- 206010017999 Gastrointestinal pain Diseases 0.000 description 1
- 208000008454 Hyperhidrosis Diseases 0.000 description 1
- 206010033645 Pancreatitis Diseases 0.000 description 1
- 229910006124 SOCl2 Inorganic materials 0.000 description 1
- 206010047700 Vomiting Diseases 0.000 description 1
- 238000006856 Wolf-Kishner-Huang Minlon reduction reaction Methods 0.000 description 1
- 238000009098 adjuvant therapy Methods 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
- KXZJHVJKXJLBKO-UHFFFAOYSA-N chembl1408157 Chemical compound N=1C2=CC=CC=C2C(C(=O)O)=CC=1C1=CC=C(O)C=C1 KXZJHVJKXJLBKO-UHFFFAOYSA-N 0.000 description 1
- 229960001701 chloroform Drugs 0.000 description 1
- OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical compound C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 description 1
- 229960001231 choline Drugs 0.000 description 1
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 description 1
- 230000008034 disappearance Effects 0.000 description 1
- BDAGIHXWWSANSR-UHFFFAOYSA-N formic acid Substances OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 230000037315 hyperhidrosis Effects 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 229910003002 lithium salt Inorganic materials 0.000 description 1
- 159000000002 lithium salts Chemical class 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000035935 pregnancy Effects 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- 239000002464 receptor antagonist Substances 0.000 description 1
- 229940044551 receptor antagonist Drugs 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- CJQOYTQOEXCVKP-UHFFFAOYSA-N sodium;9h-xanthene Chemical compound [Na].C1=CC=C2CC3=CC=CC=C3OC2=C1 CJQOYTQOEXCVKP-UHFFFAOYSA-N 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 238000007039 two-step reaction Methods 0.000 description 1
- 230000008673 vomiting Effects 0.000 description 1
- 229940118318 xanthinol Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/78—Ring systems having three or more relevant rings
- C07D311/80—Dibenzopyrans; Hydrogenated dibenzopyrans
- C07D311/82—Xanthenes
- C07D311/84—Xanthenes 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 in position 9
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/78—Ring systems having three or more relevant rings
- C07D311/80—Dibenzopyrans; Hydrogenated dibenzopyrans
- C07D311/82—Xanthenes
- C07D311/84—Xanthenes 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 in position 9
- C07D311/86—Oxygen atoms, e.g. xanthones
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a method for synthesizing xanthene-9-formic acid, belonging to the field of chemical synthesis. The method comprises the steps of reducing zinc powder into xanthene alcohol by using xanthene ketone as a raw material under an alkaline condition, then obtaining halogenated xanthene through halogenation, then obtaining 9-cyano xanthene through cyanidation under the action of a catalyst, then obtaining 9-cyano xanthene through strong alkali hydrolysis, removing organic impurities through organic solvent extraction, obtaining xanthene-9-formate aqueous solution, and then obtaining the xanthene-9-formic acid product through neutralization reaction. The method has simple operation and safe process, can obtain the xanthene-9-formic acid with high purity without refining, and is an effective method which is easy for industrial production.
Description
Technical Field
The invention belongs to the field of chemical synthesis, and relates to a synthetic method of a medical intermediate xanthene-9-formic acid.
Background
Xanthene-9-carboxylic acid (xanthene-9-carboxylic acid) is an important intermediate of M choline receptor antagonist bromamine tailin of peptic ulcer, and can also be used for synthesizing photosensitive materials, so that the xanthene-9-carboxylic acid has wide application. The bromamine tailin is mainly used for the adjuvant treatment of peptic ulcer, gastritis, pancreatitis, intestinal spasm, hyperhidrosis, vomiting of pregnancy, etc.
At present, the synthesis method of xanthene-9-formic acid mainly comprises the following methods: the method comprises the following steps:
the method comprises the following steps of (I) reducing xanthone serving as a raw material under an alkaline condition of zinc powder to obtain xanthone alcohol, and then carrying out cyanidation, hydrolysis and neutralization reaction to obtain xanthone-9-formic acid, wherein the synthetic route is as follows:
however, in the process route, a large amount of sodium cyanide needs to be used in an acetic acid system, the pH needs to be strictly controlled in large-scale production, otherwise, virulent hydrocyanic acid is generated, and serious potential safety hazards exist. Meanwhile, if the high-purity xanthene-9-formic acid is required to be obtained, acetone is required to be repeatedly recrystallized, the operation is complicated, the acetone consumption is high, and the production cost is increased.
(II) taking xanthone as a raw material, synthesizing xanthene by a Huang Minlon reduction method, and then reacting n-butyl lithium at low temperature to form salt and CO2Reacting to obtain xanthene-formate, and then performing neutralization reaction to prepare xanthene-9-formic acid. The specific synthetic route is as follows:
but in the process route, n-butyllithium is used as a strong alkali reagent, anhydrous tetrahydrofuran is used as a solvent to react at-78 ℃ to form lithium salt, and then CO is introduced at-78 to-70 DEG2The two-step reaction conditions for forming the lithium carboxylate are harsh, ultra-low temperature reaction equipment is required for mass production, and the water-free and oxygen-free reaction is strict, so the application of the lithium carboxylate is limited.
(III) reacting xanthene serving as raw material with metallic sodium to form sodium salt, and then reacting with CO at low temperature2Reacting to obtain xanthene-sodium formate, and then performing neutralization reaction to obtain xanthene-9-formic acid. The specific synthetic route is as follows:
the process uses xanthene as raw material, has high cost, needs a large amount of metal sodium reflux operation in the process of preparing xanthene sodium salt, and then carries out low temperature reaction with CO2After reaction and quenching reaction, a large amount of H is generated2And the metal sodium is very easy to ignite, and potential safety hazard exists in the use, so the route is not suitable for industrial production.
Disclosure of Invention
In order to solve the technical difficulties, the invention provides the preparation method which has mild reaction conditions, safe operation, convenient post-treatment and easy industrialization and can directly prepare the qualified product xanthene-9-formic acid without an ultralow temperature reaction device and refining.
The purpose of the invention can be realized by the following technical scheme:
a method for synthesizing xanthene-9-formic acid comprises the following steps:
(1) under alkaline conditions, carrying out reduction reaction on xanthone to obtain xanthone alcohol;
(2) performing halogenation reaction on the xanthene alcohol in the step (1) to obtain halogenated xanthene;
(3) cyaniding the halogenated xanthene in the step (2) to obtain 9-cyano xanthene;
(4) carrying out hydrolysis reaction on the 9-cyano xanthene in the step (3) to obtain xanthene-9-formate solution;
(5) and (4) extracting impurities from the xanthene-9-formate solution in the step (4) by using an organic solvent, neutralizing a water layer by using hydrochloric acid, and filtering to obtain the xanthene-9-formic acid.
The technical scheme of the invention is as follows: the reducing agent used in the reduction reaction in the step (1) is Zn; the temperature of the reduction reaction is 40-120 ℃, and the temperature of the reduction reaction is preferably 40-100 ℃.
The technical scheme of the invention is as follows: the reduction reaction time in the step (1) is 2-16 h, and the preferable reaction time is 3-6 h.
The technical scheme of the invention is as follows: the halogenating reagent selected in the halogenating reaction in the step (2) is hydrogen chloride, thionyl chloride and PCl3、PCl5Sodium bromide, PBr3And a 48% hydrobromic acid acetic acid solution; the temperature of the halogenation reaction in the step (2) is 0-120 ℃, and the preferable reaction temperature is 25-80 ℃.
The technical scheme of the invention is as follows: the solvent selected in the halogenation reaction in the step (2) is one or more of dichloromethane, trichloromethane, dichloroethane, toluene and acetic acid.
The technical scheme of the invention is as follows: the solvent selected in the cyanidation reaction in the step (3) is one or more of DMF, DMAC, DMSO and N-methylpyrrolidone.
The technical scheme of the invention is as follows: and (3) selecting one or more catalysts of CuI, NaI and KI for the cyanidation reaction.
The technical scheme of the invention is as follows: the temperature of the cyanidation reaction in the step (3) is 30-120 ℃, and the preferable reaction temperature is 60-90 ℃.
The technical scheme of the invention is as follows: the hydrolysis reaction temperature in the step (4) is 30-120 ℃, and the preferable reaction temperature is 60-100 ℃; the hydrolysis reaction time is 6-12 h.
The technical scheme of the invention is as follows: the organic solvent selected in the step (5) is one or more of dichloromethane, dichloroethane, isopropyl acetate, ethylene glycol monomethyl ether and ethylene glycol dimethyl ether.
The technical scheme of the invention is as follows: and adjusting the pH value to 1-2 through neutralization reaction.
The technical scheme of the invention is as follows: the concentration of dilute hydrochloric acid adopted in the neutralization reaction is 2-6 mol/L.
Has the advantages that: the method has the characteristics of mild reaction conditions, safe operation, no need of ultralow temperature equipment and devices, convenient post-treatment and no need of refining, and can obtain qualified products, and is an effective method with low cost and easy industrial production.
Detailed Description
The present invention is further illustrated by the following examples, but the scope of the invention is not limited thereto.
Example 1
Xanthenol synthesis
Adding xanthone (157g, 0.8mol, 1.0eq) and ethanol (1200mL) into a 2L four-neck flask, stirring at room temperature to dissolve, adding sodium hydroxide solid (160g, 4.0mol, 5.0eq), heating to 50 ℃, adding reduced Zn powder (97.5g, 1.2mol, 1.5eq) in batches, keeping the temperature for reaction for 6h after the addition is finished, and monitoring the disappearance of raw materials by TLC (V)PE/EA5: 1) after the reaction is finished, filtering to remove solid while the reaction is hot, then concentrating under reduced pressure to remove most of ethanol, adding 6mol/L dilute hydrochloric acid into the residue to adjust the pH value to 7, separating out the solid, filtering, and drying in vacuum at 50 ℃ to obtain 135g of xanthene alcohol, wherein the yield is 85.1%, and the m.p. is measured at 122-123 ℃.
9-chloro xanthene synthesis
Dissolving xanthene alcohol (49.6g, 0.25mol, 1.0eq) in DCM (200mL), cooling with ice water to 0-5 deg.C, and adding dropwise SOCl2(44.7g，0.375mol，1.5eq), dropwise adding for about 1h, then reacting for 4h at room temperature, after the reaction is finished, concentrating under reduced pressure to dryness to obtain a light yellow solid 9-chloro xanthene 43.7g with the yield of 81 percent, and measuring the m.p. at 71-73 ℃.
9-cyano xanthene synthesis
Dissolving NaCN (10.8g, 0.22mol, 1.1eq) in dry DMF (50mL), adding cuprous iodide (1.9g, 10.0mmol, 0.05eq), heating to 50 deg.C, adding 9-chloro xanthene (43.7g, 0.20mol, 1.0eq) solution in DMF (100mL) dropwise, adding dropwise for about 1h, heating to 80 deg.C, reacting for 8h, and monitoring by TLC that the raw material is basically disappeared (V)PE/EA3: 2) after the reaction is finished, cooling to room temperature, pouring the filtrate into 300mL of ice water, separating out a solid, filtering, and drying in vacuum at 40 ℃ to obtain an off-white solid 9-cyano-xanthene 36.1g with the yield of 87%, wherein the m.p. is measured to be 95-97 ℃.
Synthesis of xanthene-9-formic acid
Dissolving NaOH (64g, 1.6mol and 2.0eq) in 150mL of water, adding 9-cyano xanthene (165.6g, 0.8mol and 1.0eq) and stirring to form a suspended matter, then heating to 80 ℃, gradually changing a reaction system into a clear solution, continuously keeping the temperature and reacting for 12 hours, cooling to room temperature after the reaction is finished, adding isopropyl acetate (300mL 2) for extraction, retaining an aqueous phase xanthene-9-sodium formate aqueous solution, cooling the aqueous solution to 0-5 ℃, then adding 2mol/L dilute hydrochloric acid to adjust the pH to 1-2 while stirring, separating out a large amount of solids, continuously stirring for 1 hour, filtering, and carrying out vacuum drying at 50 ℃ to obtain 167g of white solid xanthene-9-formic acid, wherein the yield is 92.2%. The measured m.p. is 221-223 ℃, and the HPLC purity is 99.6%.
Example 2
Xanthenol synthesis
Adding xanthone (294.3g, 1.5mol, 1.0eq) and ethanol (1800mL) into a 3L four-neck flask, stirring at room temperature to dissolve, adding sodium hydroxide solid (480g, 12.0mol, 8.0eq), heating to 50 ℃, adding reduced Zn powder (195g, 3.0mol, 2.0eq) in batches, heating to reflux for 4h after the addition is finished, and monitoring by TLC that the raw materials disappear (V)PE/EA5: 1) after the reaction was completed, the solid was removed by filtration while it was hot, then most of ethanol was removed by concentration under reduced pressure, the residue was adjusted to pH 7 with 6mol/L dilute hydrochloric acid, and the solid was obtainedPrecipitating, filtering, and vacuum drying at 50 deg.C to obtain 279g of xanthinol with yield of 94%, and measuring m.p. at 122-123 deg.C.
9-bromo xanthene synthesis
Dissolving xanthene alcohol (158.6g, 0.80mol, 1.0eq) in glacial acetic acid (500mL), adding 48% HBr acetic acid solution (162g, 0.96mol, 1.2eq), heating to 50 ℃ for reaction for 3h, after the reaction is finished, concentrating under reduced pressure to dryness to obtain orange solid 9-bromine xanthene 186g with yield of 89%, and measuring m.p: 87-90 ℃.
9-cyano xanthene synthesis
Dissolving NaCN (35.3g, 0.72mol, 1.2eq) in dry DMSO (80mL), adding potassium iodide (3.0g, 10.0mmol, 0.03eq), heating to 50 ℃, then adding 9-chloro xanthene (156.7g, 0.60mol, 1.0eq) in DMSO (220mL) dropwise, adding dropwise for about 1h, heating to 80 ℃ after dropping, reacting for 8h, and monitoring by TLC that the raw material is basically disappeared (V)PE/EA3: 2) after the reaction is finished, cooling to room temperature, pouring the filtrate into 500mL of ice water, separating out a solid, filtering, and drying in vacuum at 40 ℃ to obtain an off-white solid 9-cyano-xanthene 113g with the yield of 91%, wherein the m.p. is measured at 96-97 ℃.
Synthesis of xanthene-9-formic acid
Dissolving NaOH (50g, 1.25mol and 2.5eq) in 120mL of water, adding 9-cyano xanthene (103.5g, 0.5mol and 1.0eq) and stirring to form suspended matters, then heating to 100 ℃ and refluxing, gradually changing the reaction system into a clear solution, continuously refluxing and reacting for 8 hours, cooling to room temperature after the reaction is finished, adding ethylene glycol dimethyl ether (200mL of 2) for extraction, retaining the aqueous phase xanthene-9-sodium formate aqueous solution, cooling the aqueous solution to 0-5 ℃, then adding 6mol/L dilute hydrochloric acid to adjust the pH to 1-2 while stirring, separating out a large amount of solids, continuously stirring for 1 hour, filtering, and carrying out vacuum drying at 50 ℃ to obtain 107.8g of off-white solid xanthene-9-formic acid with the yield of 95.3%. Measuring m.p: 223-224 ℃, and HPLC purity is 99.7%.
Claims (10)
1. A synthetic method of xanthene-9-formic acid is characterized by comprising the following steps: the method comprises the following steps:
(1) under alkaline conditions, carrying out reduction reaction on xanthone to obtain xanthone alcohol;
(2) performing halogenation reaction on the xanthene alcohol in the step (1) to obtain halogenated xanthene;
(3) cyaniding the halogenated xanthene in the step (2) to obtain 9-cyano xanthene;
(4) carrying out hydrolysis reaction on the 9-cyano xanthene in the step (3) to obtain xanthene-9-formate solution;
(5) extracting impurities from the xanthene-9-formate solution in the step (4) by using an organic solvent, neutralizing a water layer by using acid, and filtering to obtain xanthene-9-formic acid;
wherein: the halogenating reagent selected in the halogenating reaction in the step (2) is hydrogen chloride, thionyl chloride and PCl3、PCl5Sodium bromide, PBr3And a 48% hydrobromic acid acetic acid solution;
the temperature of the halogenation reaction in the step (2) is 25-80 ℃;
and (3) selecting one or more catalysts selected from CuI, NaI and KI in the cyanidation reaction.
2. The method of synthesizing xanthene-9-carboxylic acid as claimed in claim 1, wherein: the reducing agent used in the reduction reaction in the step (1) is Zn; the temperature of the reduction reaction is 40-120 ℃, and the time of the reduction reaction in the step (1) is 2-16 h.
3. The method of synthesizing xanthene-9-carboxylic acid as claimed in claim 2, wherein: the temperature of the reduction reaction in the step (1) is 40-100 ℃, and the reaction time is 3-6 h.
4. The method according to claim 1, wherein the solvent selected for the halogenation in step (2) is one or a mixture of several solvents selected from the group consisting of dichloromethane, chloroform, dichloroethane, toluene, and acetic acid.
5. The method of synthesizing xanthene-9-carboxylic acid as claimed in claim 1, wherein: the solvent selected in the cyanidation reaction in the step (3) is one or more of DMF, DMAC, DMSO and N-methylpyrrolidone.
6. The method of synthesizing xanthene-9-carboxylic acid as claimed in claim 1, wherein: the temperature of the cyanidation reaction in the step (3) is 30-120 ℃.
7. The method of synthesizing xanthene-9-carboxylic acid as claimed in claim 6, wherein: the reaction temperature is 60-90 ℃.
8. The method of synthesizing xanthene-9-carboxylic acid as claimed in claim 1, wherein: the hydrolysis reaction temperature in the step (4) is 30-120 ℃, and the hydrolysis reaction time is 6-12 h.
9. The method of synthesizing xanthene-9-carboxylic acid as claimed in claim 8, wherein: the hydrolysis reaction temperature in the step (4) is 60-100 ℃.
10. The method of synthesizing xanthene-9-carboxylic acid as claimed in claim 1, wherein: the organic solvent selected in the step (5) is one or more of dichloromethane, dichloroethane, isopropyl acetate, ethylene glycol monomethyl ether and ethylene glycol dimethyl ether.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2956063A (en) * | 1958-07-24 | 1960-10-11 | Burroughs Wellcome Co | Process for the manufacture of xanthene carboxylic acid derivatives |
| CN1151402A (en) * | 1995-12-05 | 1997-06-11 | 五洲药厂 | Method for prepn. of probanthine bromide and its intermediate xanthene-9-carboxylic acid |
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- 2017-06-12 CN CN201710438709.3A patent/CN107353275B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2956063A (en) * | 1958-07-24 | 1960-10-11 | Burroughs Wellcome Co | Process for the manufacture of xanthene carboxylic acid derivatives |
| CN1151402A (en) * | 1995-12-05 | 1997-06-11 | 五洲药厂 | Method for prepn. of probanthine bromide and its intermediate xanthene-9-carboxylic acid |
Non-Patent Citations (2)
| Title |
|---|
| Characterization of Tunable Piperidine and Piperazine Carbamates as Inhibitors of Endocannabinoid Hydrolases;Jonathan Z. Long等;《J. Med. Chem.》;20100125;第53卷(第4期);1830–1842 * |
| New Triazine Derivatives as Potent Modulators of Multidrug Resistance;Alain Dhainaut等;《J. Med. Chem.》;19921231;第35卷(第13期);2481-2396 * |
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