CN114539201B - Preparation method of Sibirer linking agent - Google Patents
Preparation method of Sibirer linking agent Download PDFInfo
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- CN114539201B CN114539201B CN202210198065.6A CN202210198065A CN114539201B CN 114539201 B CN114539201 B CN 114539201B CN 202210198065 A CN202210198065 A CN 202210198065A CN 114539201 B CN114539201 B CN 114539201B
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- 238000002360 preparation method Methods 0.000 title claims abstract description 10
- 238000006243 chemical reaction Methods 0.000 claims abstract description 51
- NSTREUWFTAOOKS-UHFFFAOYSA-N 2-fluorobenzoic acid Chemical compound OC(=O)C1=CC=CC=C1F NSTREUWFTAOOKS-UHFFFAOYSA-N 0.000 claims abstract description 21
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 20
- 238000005727 Friedel-Crafts reaction Methods 0.000 claims abstract description 14
- 238000010520 demethylation reaction Methods 0.000 claims abstract description 13
- DONPBOYMUMBGCQ-UHFFFAOYSA-N 7-oxabicyclo[3.3.1]nona-1(9),2,4-triene Chemical compound C1=CC(COC2)=CC2=C1 DONPBOYMUMBGCQ-UHFFFAOYSA-N 0.000 claims abstract description 11
- 238000007363 ring formation reaction Methods 0.000 claims abstract description 8
- 239000007787 solid Substances 0.000 claims description 36
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 16
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 16
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 claims description 16
- 239000000243 solution Substances 0.000 claims description 15
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 claims description 11
- 238000010791 quenching Methods 0.000 claims description 11
- 238000000034 method Methods 0.000 claims description 9
- 230000000171 quenching effect Effects 0.000 claims description 9
- 239000002904 solvent Substances 0.000 claims description 9
- 239000005457 ice water Substances 0.000 claims description 8
- 229910052757 nitrogen Inorganic materials 0.000 claims description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 8
- 239000011259 mixed solution Substances 0.000 claims description 7
- 238000005406 washing Methods 0.000 claims description 5
- 238000010438 heat treatment Methods 0.000 claims description 3
- 230000017858 demethylation Effects 0.000 abstract description 5
- 238000006798 ring closing metathesis reaction Methods 0.000 abstract description 5
- 239000007858 starting material Substances 0.000 abstract description 4
- 238000011031 large-scale manufacturing process Methods 0.000 abstract description 3
- 239000000463 material Substances 0.000 abstract description 3
- 150000001875 compounds Chemical class 0.000 abstract description 2
- 239000007788 liquid Substances 0.000 description 16
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 15
- 239000012074 organic phase Substances 0.000 description 15
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 14
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 14
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 11
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 11
- 238000001914 filtration Methods 0.000 description 10
- 238000002844 melting Methods 0.000 description 10
- 230000008018 melting Effects 0.000 description 10
- 108090000765 processed proteins & peptides Proteins 0.000 description 10
- 229920001184 polypeptide Polymers 0.000 description 9
- 102000004196 processed proteins & peptides Human genes 0.000 description 9
- 239000000047 product Substances 0.000 description 9
- 238000004537 pulping Methods 0.000 description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- 229910052799 carbon Inorganic materials 0.000 description 6
- 239000012043 crude product Substances 0.000 description 6
- 125000005647 linker group Chemical group 0.000 description 6
- 239000002841 Lewis acid Substances 0.000 description 5
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 5
- 238000005481 NMR spectroscopy Methods 0.000 description 5
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical class [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 5
- 239000007864 aqueous solution Substances 0.000 description 5
- 239000007795 chemical reaction product Substances 0.000 description 5
- 238000001816 cooling Methods 0.000 description 5
- 238000001035 drying Methods 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 239000007789 gas Substances 0.000 description 5
- 238000004128 high performance liquid chromatography Methods 0.000 description 5
- 150000007517 lewis acids Chemical class 0.000 description 5
- 238000012544 monitoring process Methods 0.000 description 5
- 239000003208 petroleum Substances 0.000 description 5
- 230000035484 reaction time Effects 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- 238000010532 solid phase synthesis reaction Methods 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 230000009286 beneficial effect Effects 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 239000003054 catalyst Substances 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- 230000006978 adaptation Effects 0.000 description 2
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 2
- 229940071870 hydroiodic acid Drugs 0.000 description 2
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- AOJFQRQNPXYVLM-UHFFFAOYSA-N pyridin-1-ium;chloride Chemical compound [Cl-].C1=CC=[NH+]C=C1 AOJFQRQNPXYVLM-UHFFFAOYSA-N 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- FEONEKOZSGPOFN-UHFFFAOYSA-K tribromoiron Chemical compound Br[Fe](Br)Br FEONEKOZSGPOFN-UHFFFAOYSA-K 0.000 description 2
- XCJHDJAODLKGLG-UHFFFAOYSA-N 3-hydroxyxanthen-9-one Chemical compound C1=CC=C2C(=O)C3=CC=C(O)C=C3OC2=C1 XCJHDJAODLKGLG-UHFFFAOYSA-N 0.000 description 1
- 208000023275 Autoimmune disease Diseases 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 229910021578 Iron(III) chloride Inorganic materials 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- ILUJQPXNXACGAN-UHFFFAOYSA-N O-methylsalicylic acid Chemical compound COC1=CC=CC=C1C(O)=O ILUJQPXNXACGAN-UHFFFAOYSA-N 0.000 description 1
- 230000001588 bifunctional effect Effects 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000002537 cosmetic Substances 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 208000030159 metabolic disease Diseases 0.000 description 1
- 239000002773 nucleotide Substances 0.000 description 1
- 125000003729 nucleotide group Chemical group 0.000 description 1
- 229920000137 polyphosphoric acid Polymers 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 208000020016 psychiatric disease Diseases 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000013341 scale-up Methods 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- BUJKNFNMGRYZBV-UHFFFAOYSA-K trifluoromethanesulfonate;ytterbium(3+);hydrate Chemical compound O.[Yb+3].[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F BUJKNFNMGRYZBV-UHFFFAOYSA-K 0.000 description 1
- 238000001291 vacuum drying Methods 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
- C07D311/86—Oxygen atoms, e.g. xanthones
-
- 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
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention provides a preparation method of a Siberian linking agent, which comprises the following steps: step 1, performing Friedel-crafts reaction on o-fluorobenzoic acid and m-benzhydryl to obtain an intermediate; and step 2, carrying out ring closure and demethylation on the intermediate to obtain the Sibir linking agent. According to the preparation method of the Siber linking agent, disclosed by the embodiment of the invention, the o-fluorobenzoic acid and the m-xylylene ether are used as starting materials, friedel-crafts reaction is firstly carried out, then the ring closure and demethylation reaction are carried out, the target compound is obtained, high-price materials are not involved in the whole reaction process, the temperature condition is relatively mild, the operability is high, the cost is low, and the Siber linking agent is suitable for safe and large-scale production.
Description
Technical Field
The invention relates to the technical field of organic synthesis, in particular to a preparation method of a Siberian linking agent.
Background
The polypeptide and protein medicines have the advantages of high activity, stable curative effect, small toxic and side effects, small dosage and the like, and have obvious curative effects and wide application prospects on cancers, autoimmune diseases, hypomnesis, mental disorder, hypertension, certain cardiovascular diseases, metabolic diseases and the like, so that the polypeptide and protein medicines are concerned by domestic and foreign experts.
The polypeptide is an important bioactive substance, and has been widely used in the fields of polypeptide medicines, polypeptide medicine carriers, peptide foods, cosmetics and the like. Currently, chemical synthesis techniques for polypeptides include both liquid phase synthesis and solid phase synthesis. The solid phase method for synthesizing polypeptide has the advantages of time saving, labor saving, material saving, convenient automation and the like, is a conventional method for synthesizing polypeptide, and has been expanded to the fields of nucleotide synthesis and other organic matters.
On the other hand, the key step in solid phase synthesis is the attachment of the target molecule to the solid support, which can be achieved by means of a cleavable linker. The linking group can be regarded as a bifunctional protecting group which is linked to the target molecule via an easily cleavable labile bond (e.g., ester bond, amide bond, etc.), on the one hand, and which in turn immobilizes the target molecule to the solid support via a relatively stable bond (e.g., carbon-carbon bond, ether bond, etc.). The selection of the desired linking group is therefore directly related to the success of the solid phase synthesis strategy.
Sieber Linker is a polypeptide synthesis linking agent with good effect, and the currently reported synthesis methods are summarized as follows:
1) The o-methoxybenzoic acid and the m-benzhydryl are subjected to Friedel-crafts reaction in polyphosphoric acid, and the intermediate and pyridine hydrochloride undergo ring closure and demethylation at a high temperature of 190 ℃ (Han, bontems, etc, journal of Organic Chemistry, 1996, vol. 61, # 18, p. 6326-6339) and the reaction equation is shown in the following formula (1):
However, this method has disadvantages in that the first-step reaction system has a large viscosity, is difficult to handle at room temperature, and has a low yield; the reaction temperature in the second step is too high, and the method is not suitable for industrial scale-up production.
2) And carrying out microwave reaction on the o-hydroxybenzoic acid and the m-diphenol under the catalysis of ytterbium triflate hydrate to obtain the Siberl linking agent. The reaction equation is shown in the following formula (2):
however, this process appears to be simple, the starting materials are also readily available, but the catalyst is expensive, resulting in excessive production costs, and the yields from the experiments are not high, and the crude product obtained is relatively difficult to purify.
Disclosure of Invention
In view of the above, the present invention aims to provide a method for preparing a siber linking agent, which has the advantages of low cost, good operability, no need of high temperature operation and suitability for safe and large-scale production.
In order to solve the technical problems, the invention adopts the following technical scheme:
the preparation method of the Sibirer linking agent provided by the embodiment of the invention comprises the following steps:
Step 1, performing Friedel-crafts reaction on o-fluorobenzoic acid and m-benzhydryl to obtain an intermediate, wherein the structural formula of the intermediate is shown as follows:
and step 2, carrying out ring closure and demethylation on the intermediate to obtain the Sibir linking agent.
Further, the friedel-crafts reaction is carried out in a solvent under the action of lewis acid.
Further, the Lewis acid is one or more of anhydrous aluminum trichloride, anhydrous ferric chloride and anhydrous ferric bromide.
Further, the step 1 includes:
step 11, o-fluorobenzoic acid is dissolved in a solvent, and m-xylylene ether is added into the solvent to obtain a mixed solution;
and step 12, slowly adding anhydrous aluminum trichloride into the mixed solution at the temperature below 10 ℃, and reacting for 4-8 hours at room temperature after the addition is finished to obtain the intermediate.
Still further, the step 1 further includes:
And 13, quenching the reaction system by ice water after the reaction is finished, and separating, washing and concentrating the product to obtain a concentrated intermediate.
Further, in the step 2, the ring-closing and demethylation reaction occurs under the action of strong acid.
Further, the strong acid is one or more of hydrobromic acid, hydrofluoric acid, hydroiodic acid and concentrated hydrochloric acid.
Still further, the step 2 includes:
adding hydrobromic acid water solution into the intermediate, heating to 80-100 ℃ under the protection of nitrogen, reacting for 6-12 hours, and performing ring closure and demethylation reaction to obtain the Sibir linking agent.
Further, in the step 2, after the reaction is finished, the solid obtained is concentrated, and recrystallized by ethanol to refine the siber linker.
The technical scheme of the invention has at least one of the following beneficial effects:
according to the preparation method of the Siber linking agent, disclosed by the embodiment of the invention, the o-fluorobenzoic acid and the m-xylylene ether are used as starting materials, friedel-crafts reaction is firstly carried out, then the ring closure and demethylation reaction are carried out, the target compound is obtained, high-price materials are not involved in the whole reaction process, the temperature condition is relatively mild, the operability is high, the cost is low, and the Siber linking agent is suitable for safe and large-scale production.
Detailed Description
In order to make the objects, technical solutions and advantages of the embodiments of the present invention more clear, the technical solutions of the present invention will be clearly and completely described below in connection with the embodiments of the present invention. It will be apparent that the described embodiments are some, but not all, embodiments of the invention. All other embodiments, which are obtained by a person skilled in the art based on the described embodiments of the invention, fall within the scope of protection of the invention.
The following first describes a preparation method of the siber linker according to an embodiment of the present invention in detail, including the following steps:
step 1, performing Friedel-crafts reaction on o-fluorobenzoic acid and m-benzhydryl to obtain an intermediate.
That is, the invention takes o-fluorobenzoic acid and m-benzhydryl as starting materials to carry out Friedel-crafts reaction to obtain an intermediate.
Specific chemical reaction formula is shown in the following formula (3):
further, the friedel-crafts reaction is carried out in a solvent under the action of lewis acid. The presence of Lewis acid can catalyze and promote the Friedel-crafts reaction.
In particular, it is preferred to use strong lewis acids, such as one or more of anhydrous aluminum trichloride, anhydrous ferric chloride, anhydrous ferric bromide.
Further, the step 1 may include:
step 11, o-fluorobenzoic acid is dissolved in a solvent, and m-xylylene ether is added into the solvent to obtain a mixed solution;
and step 12, slowly adding anhydrous aluminum trichloride into the mixed solution at the temperature below 10 ℃, and reacting for 4-8 hours at room temperature after the addition is finished to obtain the intermediate.
That is, the o-fluorobenzoic acid is firstly dissolved in a solvent, for example, in methylene dichloride, then m-xylylene ether is dissolved therein, after the mixture is uniformly mixed, anhydrous aluminum trichloride is slowly added into the mixed solution under the condition that the temperature is below 10 ℃ to be used as a catalyst for catalyzing the Friedel-crafts reaction, and after the catalyst is added, the Friedel-crafts reaction can be smoothly carried out under the room temperature condition to obtain an intermediate. The reaction condition is simple, the raw materials are low in price, the operability is strong, and the production is easy to expand.
Still further, the step 1 further includes:
And 13, quenching the reaction system by ice water after the reaction is finished, and separating, washing and concentrating the product to obtain a concentrated intermediate.
That is, after the completion of the Friedel-crafts reaction, the reaction system is separated, washed and concentrated, and the concentrated intermediate is used for the subsequent reaction. On the one hand, the method is beneficial to avoiding unnecessary side reactions, on the other hand, the method is beneficial to reducing the purification difficulty of the product, improving the yield and the like.
And step 2, carrying out ring closure and demethylation on the intermediate to obtain the Sibir linking agent.
That is, after the intermediate is obtained, the intermediate is further subjected to ring closure and demethylation to obtain the target product, that is, the siber linker.
The reaction formula is shown as the following formula (4):
further, in the step 2, the ring-closing and demethylation reaction occurs under the action of strong acid.
For example, the strong acid may be one or more of hydrobromic acid, hydrofluoric acid, hydroiodic acid, concentrated hydrochloric acid. Hydrobromic acid is preferred because of its relatively high stability, low operating conditions, and good yield.
Further, the step 2 includes:
adding hydrobromic acid water solution into the intermediate, heating to 80-100 ℃ under the protection of nitrogen, reacting for 6-12 hours, and performing ring closure and demethylation reaction to obtain the Sibir linking agent.
In addition, after the reaction is finished, the solid obtained can be concentrated, and the solid obtained is recrystallized through ethanol so as to refine the Siberian linking agent.
The preparation method of the present invention will be described in further detail with reference to the following examples.
Example 1:
In a 2L three-neck flask, 140.1g of o-fluorobenzoic acid and 1000ml of dichloromethane are added, 138.2g of m-xylylene ether is added, the temperature is reduced to 5-10 ℃, 133.3g of anhydrous aluminum trichloride is slowly added, a large amount of heat is gradually released from the system, the temperature is controlled below 10 ℃, the aluminum trichloride is slowly added, the system gradually separates out a yellow brown solid from a yellow brown clear liquid, an ice bath is removed, the reaction is carried out at room temperature for 6 hours, and TLC monitors that the o-fluorobenzoic acid is almost consumed.
After the reaction, the system was slowly added to 500g of ice water to quench the reaction, a large amount of heat and gas were released during the quenching, 500ml of 6N hydrochloric acid was added thereto, the mixture was stirred for 10 minutes, the resultant organic phase was washed once with 500ml of saturated sodium bicarbonate, the solution was separated, washed once with 500ml of saturated sodium chloride solution, the organic phase was dried over anhydrous magnesium sulfate, decolorized with activated carbon, and suction-filtered to give a pale yellow liquid, which was screwed to a large amount of white solid precipitated, 2L of petroleum ether was added thereto to be beaten for 1 hour in ice bath, suction-filtered to give a white solid, and vacuum-dried to give 210g of an intermediate (single-step molar yield 80.7%, melting point 80 ℃ or so).
210G of intermediate and 1200g of hydrobromic acid aqueous solution are added into a 2L three-neck flask, the temperature is raised to 95 ℃ for reaction for about 8 hours under the protection of nitrogen, the solid is gradually dissolved into yellow clear liquid during the reaction, and the color of the system is deeper and darker along with the lengthening of the reaction time.
TLC monitoring confirmed no intermediate and reaction was complete. The system was concentrated to precipitate a large amount of crude beige solid. The crude product is heated to reflux with 1500ml of ethanol for dissolving, decolorizing with active carbon, filtering, cooling the obtained filtrate to room temperature, adding 3000ml of water for pulping, filtering to obtain off-white to white solid, and drying in vacuum to obtain 145.5g of product (single-step molar yield 85.1%, HPLC: 98%, melting point: 251-253 ℃).
The reaction product was characterized by nuclear magnetic resonance and the data are as follows:
HNMR (400MHz, DMSO)：δ6.89(d,1H),δ6.92(dd,1H),δ7.46(td,1H),δ7.63(d,1H),δ7.77(td,1H),δ8.02(d,1H),δ8.12(dd,1H),δ11(br,OH).
example 2: in a 2L three-neck flask, 140.1g of o-fluorobenzoic acid and 1000ml of tetrahydrofuran are added, 138.2g of m-xylylene ether is added, the temperature is reduced to 5-10 ℃, 133.3g of anhydrous aluminum trichloride is slowly added, a large amount of heat is gradually released from the system, the temperature is controlled below 10 ℃, aluminum trichloride is slowly added, the system gradually separates out a yellow brown solid from a yellow brown clear liquid, an ice bath is removed, the room temperature reaction is carried out for 6 hours, and the TLC monitors that the o-fluorobenzoic acid is almost consumed.
After the reaction, cooling to below 5 ℃, concentrating tetrahydrofuran, adding 1000ml of ethyl acetate into the system, slowly dropwise adding 500g of ice water, quenching the reaction, releasing a large amount of heat and gas during the reaction, quenching, adding 500ml of 6N hydrochloric acid into the reaction, stirring for 10 minutes, separating the obtained organic phase, washing the organic phase once with 500ml of saturated sodium bicarbonate, separating the organic phase, washing the organic phase once with 500ml of saturated sodium chloride solution, separating the organic phase, drying the organic phase with anhydrous magnesium sulfate, decolorizing the active carbon, filtering the organic phase by suction to obtain a pale yellow liquid, screwing the pale yellow liquid until a large amount of white solid is separated out, adding 2L of petroleum ether into the solution, pulping the solution for 1 hour by ice bath, filtering the solution by suction to obtain a white solid, and drying the white solid by vacuum to obtain 193g of intermediate (single-step molar yield 74.2% and melting point 79 ℃).
193G of intermediate and 1200g of hydrobromic acid aqueous solution are added into a 2L three-neck flask, the temperature is raised to 95 ℃ to react for about 8 hours under the protection of nitrogen, the solid is gradually dissolved into yellow clear liquid during the reaction, and the color of the system is deeper and darker along with the lengthening of the reaction time.
TLC monitoring confirmed no intermediate and reaction was complete. The system was concentrated to precipitate a large amount of crude beige solid. The crude product is heated to reflux with 1500ml of ethanol for dissolving, decolorizing with active carbon, filtering, cooling the obtained filtrate to room temperature, adding 3000ml of water for pulping, filtering to obtain off-white to white solid, and drying in vacuum to obtain 133.7g of product (single-step molar yield 85.1%, HPLC:98.5%, melting point: 250-252 ℃).
The reaction product was characterized by nuclear magnetic resonance and the data are as follows:
HNMR (400MHz, DMSO)：δ6.89(d,1H),δ6.92(dd,1H),δ7.46(td,1H),δ7.63(d,1H),δ7.77(td,1H),δ8.02(d,1H),δ8.12(dd,1H),δ11(br,OH).
Example 3: 140.1g of o-fluorobenzoic acid and 1000ml of ethyl acetate are added into a 2L three-neck flask, 138.2g of m-xylylene ether is added into the three-neck flask, the temperature is reduced to 5-10 ℃, 133.3g of anhydrous aluminum trichloride is slowly added into the three-neck flask, a large amount of heat is gradually released from the system, the temperature is controlled below 10 ℃, aluminum trichloride is slowly added, the system gradually separates out a yellow brown solid from a yellow brown clear liquid, an ice bath is removed, the reaction is carried out for 6 hours at room temperature, and the TLC monitors that the o-fluorobenzoic acid is almost consumed.
After the reaction, the system was slowly added to 500g of ice water to quench the reaction, a large amount of heat and gas were released during the quenching, 500ml of 6N hydrochloric acid was added thereto, the mixture was stirred for 10 minutes, the resultant organic phase was washed once with 500ml of saturated sodium bicarbonate, the solution was separated, washed once with 500ml of saturated sodium chloride solution, the organic phase was dried over anhydrous magnesium sulfate, decolorized with activated carbon, and suction-filtered to give a pale yellow liquid, which was screwed to a large amount of white solid precipitated, 2L of petroleum ether was added thereto to be beaten for 1 hour in ice bath, suction-filtered to give a white solid, and vacuum-dried to give 205g of an intermediate (single-step molar yield 78.8%, melting point 79 ℃ or so).
In a 2L three-neck flask, 205g of intermediate and 1200g of hydrobromic acid aqueous solution are added, the temperature is raised to 95 ℃ for reaction for about 8 hours under the protection of nitrogen, the solid is gradually dissolved into yellow clear liquid during the reaction, and the color of the system is deeper and darker along with the lengthening of the reaction time.
TLC monitoring confirmed no intermediate and reaction was complete. The system was concentrated to precipitate a large amount of crude beige solid. The crude product is heated by 1500ml of ethanol, refluxed, dissolved, decolorized by active carbon, filtered by suction, the obtained filtrate is cooled to room temperature, and then added with 3000ml of water for pulping, filtered by suction, thus obtaining off-white to white solid, and dried in vacuum, thus obtaining 142g of product (single-step molar yield 85.1%, HPLC:99.2%, melting point: 251-253 ℃).
The reaction product was characterized by nuclear magnetic resonance and the data are as follows:
HNMR (400MHz, DMSO)：δ6.89(d,1H),δ6.92(dd,1H),δ7.46(td,1H),δ7.63(d,1H),δ7.77(td,1H),δ8.02(d,1H),δ8.12(dd,1H),δ11(br,OH).
Example 4: in a 2L three-neck flask, 140.1g of o-fluorobenzoic acid and 1000ml of acetone are added, 138.2g of m-xylylene ether is added, the temperature is reduced to 5-10 ℃, 133.3g of anhydrous aluminum trichloride is slowly added, a large amount of heat is gradually released from the system, the temperature is controlled below 10 ℃, the aluminum trichloride is slowly added, the system gradually separates out a yellow brown solid from a yellow brown clear liquid, an ice bath is removed, the reaction is carried out at room temperature for 6 hours, and TLC monitors that the o-fluorobenzoic acid is almost consumed.
After the reaction, 1000ml of dichloromethane was added to the system, 500g of ice water was slowly dropped, the reaction was quenched, a large amount of heat and gas were evolved during the quenching, 500ml of 6N hydrochloric acid was added thereto, stirring was performed for 10 minutes, the resultant organic phase was washed once with 500ml of saturated sodium bicarbonate, separated, washed once with 500ml of saturated sodium chloride solution, separated, the organic phase was dried with anhydrous magnesium sulfate, decolorized with activated carbon, suction filtered, and a pale yellow liquid was obtained, which was screwed until a large amount of white solid was precipitated, 2L of petroleum ether was added thereto, slurried with ice for 1 hour, suction filtered, and vacuum dried to obtain 201g of an intermediate (single-step molar yield 77.3%, melting point 80 ℃ or so).
201G of intermediate and 1200g of hydrobromic acid aqueous solution are added into a 2L three-neck flask, the temperature is raised to 95 ℃ to react for about 8 hours under the protection of nitrogen, the solid is gradually dissolved into yellow clear liquid during the reaction, and the color of the system is deeper and darker along with the lengthening of the reaction time.
TLC monitoring confirmed no intermediate and reaction was complete. The system was concentrated to precipitate a large amount of crude beige solid. The crude product is heated to reflux with 1500ml of ethanol for dissolving, decolorizing with active carbon, filtering, cooling the obtained filtrate to room temperature, adding 3000ml of water for pulping, filtering to obtain off-white to white solid, and drying in vacuum to obtain 139 g of product (single-step molar yield 85.1%, HPLC: 98%, melting point: 251-253 ℃).
The reaction product was characterized by nuclear magnetic resonance and the data are as follows:
HNMR (400MHz, DMSO)：δ6.89(d,1H),δ6.92(dd,1H),δ7.46(td,1H),δ7.63(d,1H),δ7.77(td,1H),δ8.02(d,1H),δ8.12(dd,1H),δ11(br,OH).
Example 5: in a 2L three-neck flask, 140.1g of o-fluorobenzoic acid and 1000ml of acetonitrile are added, 138.2g of m-xylylene ether is added, the temperature is reduced to 5-10 ℃, 133.3g of anhydrous aluminum trichloride is slowly added, a large amount of heat is gradually released from the system, the temperature is controlled below 10 ℃, the aluminum trichloride is slowly added, the system gradually separates out a yellow brown solid from a yellow brown clear liquid, an ice bath is removed, the reaction is carried out at room temperature for 6 hours, and TLC monitors that the o-fluorobenzoic acid is almost consumed.
After the reaction, 1000ml of dichloromethane was added to the system, 500g of ice water was slowly dropped, the reaction was quenched, a large amount of heat and gas were evolved during the quenching, 500ml of 6N hydrochloric acid was added thereto, stirring was performed for 10 minutes, the resultant organic phase was washed once with 500ml of saturated sodium bicarbonate, separated, washed once with 500ml of saturated sodium chloride solution, separated, the organic phase was dried with anhydrous magnesium sulfate, decolorized with activated carbon, and suction-filtered to obtain a pale yellow liquid, which was screwed to a large amount of white solid to precipitate, 2L of petroleum ether was added thereto for pulping for 1 hour in ice bath, suction-filtered to obtain a white solid, and vacuum-dried to obtain 195g of an intermediate (single-step molar yield 74.9%, melting point 79 ℃ or so).
In a 2L three-neck flask, 195g of intermediate and 1200g of hydrobromic acid aqueous solution are added, the temperature is raised to 95 ℃ for reaction for about 8 hours under the protection of nitrogen, the solid is gradually dissolved into yellow clear liquid during the reaction, and the color of the system is deeper and darker along with the lengthening of the reaction time.
TLC monitoring confirmed no intermediate and reaction was complete. The system was concentrated to precipitate a large amount of crude beige solid. The crude product is heated to reflux with 1500ml of ethanol for dissolving, decolorizing with active carbon, filtering, cooling to room temperature, adding 3000ml of water for pulping, filtering to obtain off-white to white solid, and vacuum drying to obtain 135.1g of product (single-step molar yield 85.1%, HPLC:98.9%, melting point: 250-252 ℃).
The reaction product was characterized by nuclear magnetic resonance and the data are as follows:
HNMR (400MHz, DMSO)：δ6.89(d,1H),δ6.92(dd,1H),δ7.46(td,1H),δ7.63(d,1H),δ7.77(td,1H),δ8.02(d,1H),δ8.12(dd,1H),δ11(br,OH)
While the foregoing is directed to the preferred embodiments of the present invention, it will be appreciated by those skilled in the art that various modifications and adaptations can be made without departing from the principles of the present invention, and such modifications and adaptations are intended to be comprehended within the scope of the present invention.
Claims (3)
1. The preparation method of the Siber linking agent is characterized by comprising the following steps:
Step 1, performing Friedel-crafts reaction on o-fluorobenzoic acid and m-benzhydryl to obtain an intermediate, wherein the structural formula of the intermediate is shown as follows:
，
the step 1 comprises the following steps:
step 11, o-fluorobenzoic acid is dissolved in a solvent, and m-xylylene ether is added into the solvent to obtain a mixed solution;
Step 12, slowly adding anhydrous aluminum trichloride into the mixed solution at the temperature below 10 ℃, and reacting for 4-8 hours at room temperature after the addition is finished to obtain the intermediate;
Step 2, the intermediate is subjected to ring closure and demethylation reaction to obtain the Siber linking agent, which comprises the following steps:
adding hydrobromic acid water solution into the intermediate, heating to 80-100 ℃ under the protection of nitrogen, reacting for 6-12 hours, and performing ring closure and demethylation reaction to obtain the Sibir linking agent.
2. The method of claim 1, wherein step 1 further comprises:
And 13, quenching the reaction system by ice water after the reaction is finished, and separating, washing and concentrating the product to obtain a concentrated intermediate.
3. The method according to claim 1, wherein in step 2, after the reaction is completed, the solid obtained is concentrated, and recrystallized from ethanol to refine the siber linker.
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