CN117658872A - Synthesis process of 1, 3-dihydroxy-1-p-methylsulfonyl propiophenone - Google Patents
Synthesis process of 1, 3-dihydroxy-1-p-methylsulfonyl propiophenone Download PDFInfo
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- methylsulfonyl
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- 238000000034 method Methods 0.000 title claims abstract description 24
- 230000015572 biosynthetic process Effects 0.000 title claims abstract description 6
- 238000003786 synthesis reaction Methods 0.000 title claims abstract description 6
- 238000006243 chemical reaction Methods 0.000 claims abstract description 65
- 150000001875 compounds Chemical class 0.000 claims abstract description 24
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims abstract description 24
- 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 abstract description 10
- BAPJBEWLBFYGME-UHFFFAOYSA-N Methyl acrylate Chemical compound COC(=O)C=C BAPJBEWLBFYGME-UHFFFAOYSA-N 0.000 claims abstract description 10
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 claims abstract description 9
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 6
- 239000002879 Lewis base Substances 0.000 claims abstract description 5
- CBENFWSGALASAD-UHFFFAOYSA-N Ozone Chemical compound [O-][O+]=O CBENFWSGALASAD-UHFFFAOYSA-N 0.000 claims abstract description 5
- 230000002378 acidificating effect Effects 0.000 claims abstract description 5
- 150000007527 lewis bases Chemical class 0.000 claims abstract description 5
- 238000006722 reduction reaction Methods 0.000 claims abstract description 5
- 125000004185 ester group Chemical group 0.000 claims abstract description 4
- 238000007254 oxidation reaction Methods 0.000 claims abstract description 4
- HFOCAQPWSXBFFN-UHFFFAOYSA-N 2-methylsulfonylbenzaldehyde Chemical compound CS(=O)(=O)C1=CC=CC=C1C=O HFOCAQPWSXBFFN-UHFFFAOYSA-N 0.000 claims abstract 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 abstract 5
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 51
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 38
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 30
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 27
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 15
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 13
- 230000035484 reaction time Effects 0.000 claims description 12
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 11
- 230000002194 synthesizing effect Effects 0.000 claims description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 9
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 6
- 238000004440 column chromatography Methods 0.000 claims description 6
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 claims description 6
- 238000010791 quenching Methods 0.000 claims description 5
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 4
- 239000012973 diazabicyclooctane Substances 0.000 claims description 4
- 238000007867 post-reaction treatment Methods 0.000 claims description 4
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 4
- 238000005712 Baylis-Hillman reaction Methods 0.000 claims description 3
- 239000002253 acid Substances 0.000 claims description 3
- CYTQBVOFDCPGCX-UHFFFAOYSA-N trimethyl phosphite Chemical compound COP(OC)OC CYTQBVOFDCPGCX-UHFFFAOYSA-N 0.000 claims description 3
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 claims description 2
- 239000007795 chemical reaction product Substances 0.000 claims description 2
- 125000006239 protecting group Chemical group 0.000 claims description 2
- 238000010511 deprotection reaction Methods 0.000 abstract description 2
- 238000002360 preparation method Methods 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- DRSHXJFUUPIBHX-UHFFFAOYSA-N COc1ccc(cc1)N1N=CC2C=NC(Nc3cc(OC)c(OC)c(OCCCN4CCN(C)CC4)c3)=NC12 Chemical compound COc1ccc(cc1)N1N=CC2C=NC(Nc3cc(OC)c(OC)c(OCCCN4CCN(C)CC4)c3)=NC12 DRSHXJFUUPIBHX-UHFFFAOYSA-N 0.000 description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- 238000001514 detection method Methods 0.000 description 5
- 239000012074 organic phase Substances 0.000 description 5
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- 239000003921 oil Substances 0.000 description 4
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 3
- 239000012267 brine Substances 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 230000000171 quenching effect Effects 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 238000001308 synthesis method Methods 0.000 description 3
- AYIRNRDRBQJXIF-NXEZZACHSA-N (-)-Florfenicol Chemical compound CS(=O)(=O)C1=CC=C([C@@H](O)[C@@H](CF)NC(=O)C(Cl)Cl)C=C1 AYIRNRDRBQJXIF-NXEZZACHSA-N 0.000 description 2
- PSVPUHBSBYJSMQ-UHFFFAOYSA-N 4-methylsulfonylbenzaldehyde Chemical compound CS(=O)(=O)C1=CC=C(C=O)C=C1 PSVPUHBSBYJSMQ-UHFFFAOYSA-N 0.000 description 2
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 2
- 239000012230 colorless oil Substances 0.000 description 2
- 230000032798 delamination Effects 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 229960003760 florfenicol Drugs 0.000 description 2
- 239000000499 gel Substances 0.000 description 2
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- OTVAEFIXJLOWRX-NXEZZACHSA-N thiamphenicol Chemical compound CS(=O)(=O)C1=CC=C([C@@H](O)[C@@H](CO)NC(=O)C(Cl)Cl)C=C1 OTVAEFIXJLOWRX-NXEZZACHSA-N 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- HIZVCIIORGCREW-UHFFFAOYSA-N 1,4-dioxene Chemical compound C1COC=CO1 HIZVCIIORGCREW-UHFFFAOYSA-N 0.000 description 1
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 1
- 208000007976 Ketosis Diseases 0.000 description 1
- 101710164401 Omega-aminotransferase Proteins 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 238000005903 acid hydrolysis reaction Methods 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical class OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 229960005091 chloramphenicol Drugs 0.000 description 1
- WIIZWVCIJKGZOK-RKDXNWHRSA-N chloramphenicol Chemical compound ClC(Cl)C(=O)N[C@H](CO)[C@H](O)C1=CC=C([N+]([O-])=O)C=C1 WIIZWVCIJKGZOK-RKDXNWHRSA-N 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- CDHICTNQMQYRSM-UHFFFAOYSA-N di(propan-2-yl)alumane Chemical compound CC(C)[AlH]C(C)C CDHICTNQMQYRSM-UHFFFAOYSA-N 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 238000000589 high-performance liquid chromatography-mass spectrometry Methods 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 150000002584 ketoses Chemical class 0.000 description 1
- 238000006138 lithiation reaction Methods 0.000 description 1
- 229910003002 lithium salt Inorganic materials 0.000 description 1
- 159000000002 lithium salts Chemical class 0.000 description 1
- UBJFKNSINUCEAL-UHFFFAOYSA-N lithium;2-methylpropane Chemical compound [Li+].C[C-](C)C UBJFKNSINUCEAL-UHFFFAOYSA-N 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000006385 ozonation reaction Methods 0.000 description 1
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 1
- 238000007142 ring opening reaction Methods 0.000 description 1
- 238000013341 scale-up Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 1
- 229960003053 thiamphenicol Drugs 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
The invention discloses a synthesis process of 1, 3-dihydroxy-1-p-methylsulfonyl propiophenone, which comprises the following steps: (1) Under the action of Lewis base, methyl sulfonyl benzaldehyde and methyl acrylate are reacted to obtain an intermediate III; (2) Under the action of imidazole, performing hydroxyl protection reaction on an intermediate III and TBSCl to obtain a compound IV; (3) The compound IV and DIBAL-H undergo an ester group reduction reaction to obtain a compound V; (4) Under the action of imidazole, performing hydroxyl protection reaction on the compound V and TBSCl to obtain a compound VI; (5) Carrying out oxidation reaction on the compound VI under the action of ozone to obtain a compound II; (6) The compound II is subjected to deprotection under an acidic condition to obtain a compound I, namely the 1, 3-dihydroxy-1-p-methylsulfonyl propiophenone.
Description
Technical Field
The invention relates to a preparation method of a florfenicol intermediate, in particular to a synthesis method of 1, 3-dihydroxy-1-p-methylsulfonyl propiophenone.
Background
Florfenicol is a monofluoro derivative of artificially synthesized thiamphenicol, and is a novel broad-spectrum antibacterial agent of chloramphenicol special for veterinarian successfully developed in the late eighties.
The functional group of dihydroxyketones is not only present in natural products, but is also an important synthetic fragment of synthetic ketoses.
WO2022166838 can convert 1, 3-dihydroxy-1-p-methylsulfonyl-propiophenone to chiral 1, 3-dihydroxy-2-amino-1-p-methylsulfonyl-phenylpropane by the omega-aminotransferase ATA117 mutant. This provides a new synthetic method for synthesizing thiamphenicol analogs. However, fewer methods exist for synthesizing 1, 3-dihydroxy-1-p-methylsulfonyl propiophenone.
The similar synthesis method comprises the following steps:
1) The 1, 3-dihydroxy-1-propiophenone is obtained by column chromatography after five steps of reactions including lithiation, condensation, oxidation, reduction ring opening and acid hydrolysis by taking 1, 4-dioxa-cyclohexene as a starting material (Tetrahedron Lett,1985, 26 (40), 4925-4928). The yield thereof was found to be 18.6%.
The route has low yield through five steps of reactions, and uses more expensive reagents such as tert-butyllithium, sodium borohydride and m-chloroperoxybenzoic acid. Meanwhile, the first two steps need low-temperature reaction, and the last step uses column chromatography for purification.
2) In addition, a simple synthesis method has been reported, in which a reaction between 1eq of lithium salt (3 mmol) and 3eq of benzaldehyde is effected on tertiary amine, column chromatography purification is required, carbonyl-transferred isomer is easily formed, and separation is not easy. And cannot be prepared in scale-up (Eur. J. Org. Chem,2006, 1121-1123).
The method has the advantages of complex operation, low yield, long production period and no contribution to industrial production.
Disclosure of Invention
Aiming at the problems in the technology, the invention provides a novel method for preparing 1, 3-dihydroxy-1-p-methylsulfonyl propiophenone, which improves the yield of the product, and the highest yield reaches 77.5 percent, and the post-treatment is simple.
The technical scheme of the invention is as follows:
a synthesis process of 1, 3-dihydroxy-1-p-methylsulfonyl propiophenone comprises the following steps:
(1) Under the action of Lewis base, carrying out Baylis-Hillman reaction on methylsulfonyl benzaldehyde and methyl acrylate to obtain an intermediate III;
(2) Under the action of imidazole, performing hydroxyl protection reaction on an intermediate III and TBSCl to obtain a compound IV;
(3) The compound IV and DIBAL-H undergo an ester group reduction reaction to obtain a compound V;
(4) Under the action of imidazole, performing hydroxyl protection reaction on the compound V and TBSCl to obtain a compound VI;
(5) Carrying out oxidation reaction on the compound VI under the action of ozone to obtain a compound II;
(6) Removing protecting groups from the compound II under an acidic condition to obtain a compound I, namely the 1, 3-dihydroxy-1-p-methylsulfonyl propiophenone;
the reaction formula is as follows:
preferably, in step (1), the reaction is performed in at least one of tetrahydrofuran, acetonitrile, DMF, DMSO, and more preferably tetrahydrofuran.
In the step (1), the lewis base is at least one of DABCO (triethylenediamine), triethylamine and triphenylphosphine, and more preferably DABCO.
In the step (1), the reaction temperature is 20-50 ℃ and the reaction time is 12-36 h.
In the step (1), the post-treatment process is as follows:
the reaction solution is concentrated, then ethyl acetate and hydrochloric acid are added, the mixture is stirred and then is stood for layering, the organic phase is washed by brine, and the intermediate III is obtained by concentration.
Preferably, in step (2), the reaction is carried out in at least one of dichloromethane, tetrahydrofuran, ethyl acetate and toluene, and more preferably dichloromethane.
In the step (2), the reaction temperature is 0-10 ℃ and the reaction time is 12-36 h.
In the step (2), the post-reaction treatment process is as follows:
the reaction was quenched with water, allowed to stand for delamination, the organic phase was washed with brine, toluene was then added, and concentrated to give the compound IV.
Preferably, in step (3), the reaction is carried out in at least one of dichloromethane, tetrahydrofuran, ethyl acetate and toluene, and more preferably dichloromethane.
In the step (3), the reaction temperature is between-5 and-20 ℃ and the reaction time is between 0.5 and 5 hours.
In the step (3), the post-treatment process after the reaction is finished is as follows:
quenching the reaction by adding water, stirring to form white gel, filtering, washing with dichloromethane, and concentrating the filtrate to dryness to obtain the compound V;
preferably, in step (4), the reaction is carried out in at least one of dichloromethane, tetrahydrofuran, ethyl acetate, toluene;
in the step (4), the reaction temperature is 0-10 ℃ and the reaction time is 12-36 h.
In the step (4), the post-reaction treatment process is as follows:
the reaction was quenched with water, allowed to stand for delamination, the organic phase was washed with brine, toluene was then added, and concentrated to give the compound IV.
Preferably, in step (5), the reaction is carried out in methanol or tetrahydrofuran, more preferably methanol;
in the step (5), the reaction temperature is-70 to-80 ℃ and the reaction time is 20 to 60min.
In the step (5), the post-reaction treatment process is as follows:
adding trimethyl phosphite to quench the reaction, concentrating the reaction product under reduced pressure to be dry, and carrying out column chromatography to obtain the compound II.
Preferably, in step (6), the reaction is carried out in a mixed system of THF and water;
the acid used in the acidic condition is acetic acid, and other acids are adopted to react with poor effect. Further, THF, H 2 The volume ratio of O to AcOH is 1:1.0 to 1.2:3.0 to 3.6.
In the step (6), the reaction temperature is 10-30 ℃ and the reaction time is 10-30 h.
In the step (6), the post-treatment process is as follows:
the reaction solution is concentrated to dryness under reduced pressure, and then dichloromethane is added to the mixture to stir, filter, wash and dry the mixture to obtain the compound I.
Compared with the prior art, the invention has the following technical effects:
according to the invention, p-methylsulfonyl benzaldehyde and methyl acrylate are used as raw materials, and 1, 3-dihydroxy-1-p-methylsulfonyl propiophenone is obtained through the steps of Baylis-Hillman reaction, hydroxyl TBS protection, ester group reduction, TBSCl protection, ozonization reaction and deprotection in sequence, the whole reaction route has mild reaction conditions and simple post-treatment, the yield of each step is higher, and the yield of the whole route is obviously improved.
Detailed Description
Example 1
1) Preparation of Compound III
Tetrahydrofuran (20 mL) was added to a 100mL three-necked flask at 20-30deg.C, stirring was turned on, and methyl acrylate (12.9 g,0.15 mol), p-methylsulfonyl benzaldehyde (18.4 g,0.10 mol) and DABCO (2.2 g,0.02 mol) were further added. The reaction was carried out at room temperature for 1 day. TLC detects complete reaction of starting material.
Concentrated to dryness under reduced pressure at 40℃to the concentrated solution were added 100mL of ethyl acetate and 50mL of hydrochloric acid (1M), and the mixture was stirred for 10 minutes. Standing and layering. Saturated saline (50 mL) was used for washing. Concentrated to dryness under reduced pressure to give 27.0g of a pale yellow oil in 100% yield. Directly used in the next reaction.
2) Preparation of Compound IV
The compound III obtained in the previous step is dissolved in 100mL of dichloromethane, added into a 250mL reaction bottle, and stirring is started. Imidazole (18.0 g) was added followed by TBSCl (23.8 g) slowly by controlling the temperature at 0-10 ℃. The reaction was carried out overnight. TLC detection reaction was complete.
Controlling the temperature to be 0-10 ℃, and adding 40mL of water for quenching. The solid was completely dissolved. Standing and layering. The organic phase was washed with saturated brine (40 mL). Toluene (50 mL) was added and the solution was concentrated again to dryness. 34.2g of a pale yellow oil was obtained.
3) Preparation of Compound V
Compound IV (7.3 g,0.019 mol) was dissolved in 60mL of methylene chloride, transferred to a 250mL three-necked flask, purged 3 times with nitrogen, cooled to-10℃and DIBAL-H diisopropylaluminum hydride (15 mL,0.023 mol) was added. The addition was completed for about 30 minutes. And (3) reacting for 2 hours, and finishing the reaction of the raw materials.
10mL of water was added and quenched, and stirred for 1h to form a white gel, which was filtered. 30mL of dichloromethane. The filtrate was concentrated to dryness to give 6.7g of a colorless oil. Directly used in the next reaction.
4) Preparation of Compound VI
Compound V (6.7 g,0.019 mol) obtained in the above step was dissolved in 100mL of methylene chloride, and added to a 250mL reaction flask, and stirring was started. Imidazole (2.7 g) was added followed by TBSCl (3.62 g) slowly by controlling the temperature at 0-10 ℃. The reaction was carried out overnight. TLC detection reaction was complete.
Controlling the temperature to be 0-10 ℃, and adding 10mL of water for quenching. The solid was completely dissolved. Standing and layering. The organic phase was washed with saturated brine (20 mL). Toluene (30 mL) was added and the solution was concentrated again to dryness. 8.05g of a pale yellow oil was obtained.
5) Preparation of Compound II
Compound VI (8.05 g) obtained in the previous step was dissolved in methanol (50 mL), replaced with nitrogen, cooled to-78deg.C, ozone was introduced, and the solution turned blue in color for about 30 minutes. TLC detection, complete reaction of starting material. Quenched by addition of 2.0g trimethyl phosphite. And removing ozone by nitrogen substitution. The resulting solution was concentrated to dryness under reduced pressure at 40 ℃. 9.2g of an oil was obtained.
Silica gel column chromatography (n-heptane/ethyl acetate=10:1) afforded 8.0g of colorless oil as compound II, which became a waxy solid after standing. The total yield of the first five steps is 79%.
1 H NMR(CDCl 3 ，500MHz)δ-0.005(t,9H),0.11(s,3H),0.90(t，9H)0.95(s，9H)，3.03(s，3H)，4.59(dd，2H)，5.32(s，1H)，7.65(d，2H)，7.92(d，2H)ppm.
13 C NMR(CDCl 3 ，125MHz)δ-5.55,-5.25，-4.94,18.18,18.46,25.66,25.74,44.53,66.06,79.09,126.87,127.67,140.31,144.62,207.01ppm.
6) Preparation of Compound I
To compound II (4.0 g,0.008 mol) was added THF (10 mL) and stirred for 10 min. Into a 250mL reaction flask, acetic acid (30 mL) and water (10 mL) were added at a temperature of 10-20deg.C. The reaction was incubated at room temperature for 18h. TLC detection was complete. The reaction was stopped. Concentrated to dryness under reduced pressure to give 3.0g of an off-white solid.
Dichloromethane (40 mL) was added and stirred for 2h. Filtered and washed with dichloromethane. 2.1g of wet product are obtained, and 1.8g of compound of formula I is obtained as a white solid by vacuum drying at 40 ℃. The yield thereof was found to be 87.1%.
1 H NMR(CDCl 3 ，500MHz)δ3.14(s,1H),3.29-3.31(m,2H),3.56(d,1H),3.86(d,1H),7.89-7.91(m,2H),7.96-7.97(m,2H).
HPLC-MS(M-1):243.0。
Example 2
The other steps are the same as in example 1, step 6) proceeds as follows:
preparation of Compound I
To compound II (2.0 g,0.004 mol) was added THF (5 mL) and stirred for 10 minutes to dissolve completely. Into a 50mL reaction flask, under nitrogen protection, a tetrahydrofuran solution (17 mL) of TBAF (1M) was added at a temperature of 10-20deg.C. The reaction was incubated at room temperature for 2h. TLC detection was complete. The reaction was stopped. Concentrating under reduced pressure to dry.
Purification by column chromatography on silica gel eluting with methylene chloride/methanol/THF (40:1:10) gave 0.55g of a white solid in 53.2% yield.
Claims (10)
1. The synthesis process of 1, 3-dihydroxy-1-p-methylsulfonyl propiophenone is characterized by comprising the following steps:
(1) Under the action of Lewis base, carrying out Baylis-Hillman reaction on methylsulfonyl benzaldehyde and methyl acrylate to obtain an intermediate III;
(2) Under the action of imidazole, performing hydroxyl protection reaction on an intermediate III and TBSCl to obtain a compound IV;
(3) The compound IV and DIBAL-H undergo an ester group reduction reaction to obtain a compound V;
(4) Under the action of imidazole, performing hydroxyl protection reaction on the compound V and TBSCl to obtain a compound VI;
(5) Carrying out oxidation reaction on the compound VI under the action of ozone to obtain a compound II;
(6) Removing protecting groups from the compound II under an acidic condition to obtain a compound I, namely the 1, 3-dihydroxy-1-p-methylsulfonyl propiophenone;
the reaction formula is as follows:
2. the process for synthesizing 1, 3-dihydroxy-1-p-methylsulfonyl propiophenone according to claim 1, wherein in step (1), the reaction is performed in at least one of tetrahydrofuran, acetonitrile, DMF, DMSO;
the Lewis base is at least one of DABCO, triethylamine and triphenylphosphine;
in the step (1), the reaction temperature is 20-50 ℃ and the reaction time is 12-36 h.
3. The process for synthesizing 1, 3-dihydroxy-1-p-methylsulfonyl propiophenone according to claim 1, wherein in step (2), the reaction is performed in at least one of dichloromethane, tetrahydrofuran, ethyl acetate, toluene;
in the step (2), the reaction temperature is 0-10 ℃ and the reaction time is 12-36 h.
4. The process for synthesizing 1, 3-dihydroxy-1-p-methylsulfonyl propiophenone according to claim 1, wherein in step (3), the reaction is performed in at least one of dichloromethane, tetrahydrofuran, ethyl acetate, toluene;
in the step (3), the reaction temperature is between-5 and-20 ℃ and the reaction time is between 0.5 and 5 hours.
5. The process for synthesizing 1, 3-dihydroxy-1-p-methylsulfonyl propiophenone according to claim 1, wherein in step (4), the reaction is performed in at least one of dichloromethane, tetrahydrofuran, ethyl acetate, toluene;
in the step (4), the reaction temperature is 0-10 ℃ and the reaction time is 12-36 h.
6. The process for the synthesis of 1, 3-dihydroxy-1-p-methylsulfonyl propiophenone according to claim 1, wherein in step (5), the reaction is carried out in methanol or tetrahydrofuran.
7. The process for synthesizing 1, 3-dihydroxy-1-p-methylsulfonyl propiophenone according to claim 1, wherein in step (5), the reaction temperature is-70 to-80 ℃ and the reaction time is 20-60 min.
8. The process for synthesizing 1, 3-dihydroxy-1-p-methylsulfonyl propiophenone according to claim 1, wherein in step (5), the post-reaction treatment process is as follows:
adding trimethyl phosphite to quench the reaction, concentrating the reaction product under reduced pressure to be dry, and carrying out column chromatography to obtain the compound II.
9. The process for synthesizing 1, 3-dihydroxy-1-p-methylsulfonyl propiophenone according to claim 1, wherein in step (6), the reaction is performed in a mixed system of THF and water;
the acid used in the acidic condition is acetic acid.
10. The process for synthesizing 1, 3-dihydroxy-1-p-methylsulfonyl propiophenone according to claim 1, wherein in step (6), the reaction temperature is 10-30 ℃ and the reaction time is 10-30 h.
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