CN118027055A - Preparation method of key intermediate of Ai Li brines compound - Google Patents
Preparation method of key intermediate of Ai Li brines compound Download PDFInfo
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- CN118027055A CN118027055A CN202211358638.3A CN202211358638A CN118027055A CN 118027055 A CN118027055 A CN 118027055A CN 202211358638 A CN202211358638 A CN 202211358638A CN 118027055 A CN118027055 A CN 118027055A
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 144
- 238000002360 preparation method Methods 0.000 title claims description 7
- 239000000203 mixture Substances 0.000 claims abstract description 39
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 36
- 239000006227 byproduct Substances 0.000 claims abstract description 31
- 238000000034 method Methods 0.000 claims abstract description 26
- 238000004519 manufacturing process Methods 0.000 claims abstract description 12
- 230000008569 process Effects 0.000 claims abstract description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 7
- 239000012046 mixed solvent Substances 0.000 claims abstract description 5
- 238000006243 chemical reaction Methods 0.000 claims description 41
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 39
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 claims description 21
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 18
- 230000002378 acidificating effect Effects 0.000 claims description 16
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 16
- 150000002500 ions Chemical class 0.000 claims description 16
- 239000011347 resin Substances 0.000 claims description 16
- 229920005989 resin Polymers 0.000 claims description 16
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 15
- 125000000217 alkyl group Chemical group 0.000 claims description 15
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 claims description 14
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 12
- 239000002585 base Substances 0.000 claims description 8
- 238000004440 column chromatography Methods 0.000 claims description 8
- 229920001467 poly(styrenesulfonates) Polymers 0.000 claims description 8
- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 8
- 125000003118 aryl group Chemical group 0.000 claims description 7
- 229910000019 calcium carbonate Inorganic materials 0.000 claims description 7
- 239000000706 filtrate Substances 0.000 claims description 7
- 125000006239 protecting group Chemical group 0.000 claims description 7
- -1 silyl hydroxy protecting group Chemical group 0.000 claims description 7
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 6
- 125000005233 alkylalcohol group Chemical group 0.000 claims description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 6
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical group N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 5
- 239000000047 product Substances 0.000 claims description 5
- 125000004641 (C1-C12) haloalkyl group Chemical group 0.000 claims description 4
- 230000001476 alcoholic effect Effects 0.000 claims description 4
- 150000001412 amines Chemical class 0.000 claims description 4
- 239000003999 initiator Substances 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 4
- 239000003513 alkali Substances 0.000 claims description 3
- 238000001914 filtration Methods 0.000 claims description 3
- ZBLLGPUWGCOJNG-UHFFFAOYSA-N Halichondrin B Natural products CC1CC2(CC(C)C3OC4(CC5OC6C(CC5O4)OC7CC8OC9CCC%10OC(CC(C(C9)C8=C)C%11%12CC%13OC%14C(OC%15CCC(CC(=O)OC7C6C)OC%15C%14O%11)C%13O%12)CC%10=C)CC3O2)OC%16OC(CC1%16)C(O)CC(O)CO ZBLLGPUWGCOJNG-UHFFFAOYSA-N 0.000 claims description 2
- 229910021529 ammonia Inorganic materials 0.000 claims description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
- FXNFULJVOQMBCW-VZBLNRDYSA-N halichondrin b Chemical compound O([C@@H]1[C@@H](C)[C@@H]2O[C@@H]3C[C@@]4(O[C@H]5[C@@H](C)C[C@@]6(C[C@@H]([C@@H]7O[C@@H](C[C@@H]7O6)[C@@H](O)C[C@@H](O)CO)C)O[C@H]5C4)O[C@@H]3C[C@@H]2O[C@H]1C[C@@H]1C(=C)[C@H](C)C[C@@H](O1)CC[C@H]1C(=C)C[C@@H](O1)CC1)C(=O)C[C@H](O2)CC[C@H]3[C@H]2[C@H](O2)[C@@H]4O[C@@H]5C[C@@]21O[C@@H]5[C@@H]4O3 FXNFULJVOQMBCW-VZBLNRDYSA-N 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims 1
- 125000000037 tert-butyldiphenylsilyl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1[Si]([H])([*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims 1
- 238000011084 recovery Methods 0.000 abstract description 4
- 229930195695 Halichondrin Natural products 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 238000006482 condensation reaction Methods 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- 125000000025 triisopropylsilyl group Chemical group C(C)(C)[Si](C(C)C)(C(C)C)* 0.000 description 4
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 3
- DCERHCFNWRGHLK-UHFFFAOYSA-N C[Si](C)C Chemical compound C[Si](C)C DCERHCFNWRGHLK-UHFFFAOYSA-N 0.000 description 3
- 150000004703 alkoxides Chemical class 0.000 description 3
- 235000011114 ammonium hydroxide Nutrition 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 125000001072 heteroaryl group Chemical group 0.000 description 3
- 238000005935 nucleophilic addition reaction Methods 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- RRKTZKIUPZVBMF-IBTVXLQLSA-N brucine Chemical compound O([C@@H]1[C@H]([C@H]2C3)[C@@H]4N(C(C1)=O)C=1C=C(C(=CC=11)OC)OC)CC=C2CN2[C@@H]3[C@]41CC2 RRKTZKIUPZVBMF-IBTVXLQLSA-N 0.000 description 2
- RRKTZKIUPZVBMF-UHFFFAOYSA-N brucine Natural products C1=2C=C(OC)C(OC)=CC=2N(C(C2)=O)C3C(C4C5)C2OCC=C4CN2C5C31CC2 RRKTZKIUPZVBMF-UHFFFAOYSA-N 0.000 description 2
- KPUWHANPEXNPJT-UHFFFAOYSA-N disiloxane Chemical compound [SiH3]O[SiH3] KPUWHANPEXNPJT-UHFFFAOYSA-N 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 125000001033 ether group Chemical group 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 125000003808 silyl group Chemical group [H][Si]([H])([H])[*] 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 206010006187 Breast cancer Diseases 0.000 description 1
- 239000007848 Bronsted acid Substances 0.000 description 1
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- KRHYYFGTRYWZRS-UHFFFAOYSA-M Fluoride anion Chemical compound [F-] KRHYYFGTRYWZRS-UHFFFAOYSA-M 0.000 description 1
- 239000004721 Polyphenylene oxide Substances 0.000 description 1
- BLRPTPMANUNPDV-UHFFFAOYSA-N Silane Chemical group [SiH4] BLRPTPMANUNPDV-UHFFFAOYSA-N 0.000 description 1
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical group [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 201000010386 breast liposarcoma Diseases 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- UFNVPOGXISZXJD-XJPMSQCNSA-N eribulin Chemical compound C([C@H]1CC[C@@H]2O[C@@H]3[C@H]4O[C@H]5C[C@](O[C@H]4[C@H]2O1)(O[C@@H]53)CC[C@@H]1O[C@H](C(C1)=C)CC1)C(=O)C[C@@H]2[C@@H](OC)[C@@H](C[C@H](O)CN)O[C@H]2C[C@@H]2C(=C)[C@H](C)C[C@H]1O2 UFNVPOGXISZXJD-XJPMSQCNSA-N 0.000 description 1
- 229960003649 eribulin Drugs 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 150000004673 fluoride salts Chemical class 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 239000003120 macrolide antibiotic agent Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 238000007747 plating Methods 0.000 description 1
- 229920000570 polyether Polymers 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical group C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 description 1
- 238000006257 total synthesis reaction Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
A process for preparing Ai Li a key intermediate of Brin, in which, when compound (9) is prepared from compound (7) via intermediate compound (13) and compound (8), a mixture of by-products is produced, which comprises compounds (8 a), (8 b) and/or (8 c), the process according to the invention, after recovery of the by-products, is dissolved in a mixed solvent of alcohol and water, which is converted into compound (8) in the presence of a base, and compound (8) is prepared again as compound (9),
Description
Technical Field
The invention relates to a preparation method of a key intermediate compound which can be used for preparing halichondrin analogues, in particular Ai Li bucin, belonging to the technical field of organic synthesis.
Background
Halichondrin (Halichondrin, hereinafter referred to as HB) is a natural product with polyether macrolide structure existing in cavernous body, and has strong anti-tumor effect and wide medicinal prospect. Ai Li Boolean (Eribulin, EB) is a structurally simplified analog of halichondrin, and has been used clinically at present to treat advanced breast cancer and liposarcoma.
Neither HB nor EB are available in large quantities from natural sources, but rely on artificial synthesis. Ai Li the structure of the brucine is complex, the molecule of the brucine contains 19 chiral carbon atoms, the total synthesis route used at present is up to 62 steps, so that the labor cost in production is very large, and the influence of the yield on the cost is more critical when the yield is more and more advanced.
In the prior art, the process for the conversion of intermediate compound (7) to compound (9) for the preparation of Ai Li brin is shown below:
Firstly, removing 5 TBS protecting groups of the compound (7) under the action of tetrabutylammonium fluoride to generate an intermediate (13); both C8-OH and C9-OH of the intermediate (13) can carry out 1, 4-nucleophilic addition reaction on alpha, beta-unsaturated ketone: c12-beta compound (8 b) and C12-alpha compound (8C) can be obtained by nucleophilic addition reaction of C8-OH, C12-beta compound (8) and C12-alpha compound (8 a) can be obtained by nucleophilic addition reaction of C9-OH; of the four compounds, only the C8-OH and C11-OH groups in the compound (8) are spatially close to the carbonyl groups of the C14 due to steric hindrance, and condensation reaction can occur under the catalysis of acid to generate the target compound (9). The condensation reaction of the compound (8 a), the compound (8 b) and the compound (8 c) cannot be carried out, so that the condensation reaction is kept unchanged in a reaction system, and finally the condensation reaction is separated and removed as a by-product through column chromatography, wherein the total amount of the by-product can reach 15% -25% of the total product amount, and huge material waste is caused. If a method can be developed, the generation of byproducts is reduced, and the byproducts are converted into target compounds (9) as much as possible, the yield of the reaction is greatly improved, and the material cost of the whole synthesis process is reduced, so that the method has great advantages.
Disclosure of Invention
The present invention provides a method for synthesizing a compound (9) from a compound (7), which treats a by-product (8 a), a compound (8 b), and a compound (8 c) generated in a reaction, effectively promotes its conversion into a compound (8), and finally into a compound (9).
The technical scheme of the invention is as follows:
a process for preparing compound (8), the process comprising:
(1) The compound (7) is converted into the compound (8) via the intermediate compound (13) as follows,
(2) Dissolving the by-product mixture produced from the above compounds (7) to (8) in a mixed solvent of alcohol and water, and reconverting into the compound (8) in the presence of a base, wherein the by-product mixture comprises one, two or three of the following compounds (8 a), (8 b) and (8 c),
Wherein R 1 is R OR, R is hydrogen, C 1-12 haloalkyl, C 1-12 alkyl optionally substituted with aryl, preferably, the C 1-12 haloalkyl, C 1-12 alkyl is preferably C 1-4 alkyl, the aryl substituted C 1-12 alkyl is phenyl substituted C 1-4 alkyl, such as benzyl, the PGs are each independently selected from the same OR different hydroxy protecting groups, preferably a silyl hydroxy protecting group, such as TMS, TES, TBS (TBDMS), TBDPS, TIPS, TPS.
According to an embodiment of the invention, in step (2), the base is selected from ammonia or amines. The amines of the invention are preferably: RNH 2,R2NH,R3 N, wherein R is C 1-6 alkyl.
According to an embodiment of the invention, in step (2), the alcohol is selected from the group consisting of C 1-6 alkyl alcohols, of which methanol, ethanol, isopropanol or a mixed alcohol thereof is preferred.
According to an embodiment of the invention, in step (2), the volume ratio of alcohol to water is from 1:2 to 2:1, preferably 1:1.
According to an embodiment of the invention, in step (2), the reaction is carried out at 0-50 ℃, preferably 0-30 ℃.
According to an embodiment of the invention, in step (2), the mass ratio of base to by-product mixture is from 1:1 to 1:8, preferably from 1:4 to 1:5.
According to an embodiment of the invention, in step (2), the conversion time is more than 8 hours, preferably 12-24 hours.
According to an embodiment of the present invention, in step (2), after the completion of the reaction, the alkali and the solvent are removed by simple treatment, for example, by concentrating under reduced pressure.
In the present invention, in the step (2), the reaction system is formed in the following manner: the byproduct mixture is dissolved in alcohol and then aqueous alkali is added.
"Hydroxy protecting group" as used herein means any group capable of protecting the oxygen atom to which it is attached from reaction or bonding. These hydroxyl protecting groups are known in the art. Exemplary hydroxyl protecting groups include, but are not limited to, formation with protected oxygen: acyl, ester, carbonate, carbamate, sulfonate, and ether groups. For example, the hydroxyl protecting group forms a silyl ether with oxygen, the silicon group preferably being a silyl group or a substituted silyl group, the substituent being selected from halogen. The protecting group for the silane group is, for example: tri (C 1-6 alkyl) silyl, tri (C 6-10 aryl or C 1-6 heteroaryl) silyl, di (C 6-10 aryl or C 1-6 heteroaryl) (C 1-6 alkyl) silyl, and (C 6-10 aryl or C 1-6 heteroaryl) di (C 1-6 alkyl) silyl), specific examples include Trimethylsilyl (TMS), triethylsilyl (TES), t-butyldimethylsilyl (TBS), t-butyldiphenylsilyl (TBDPS), triisopropylsilyl (TIPS), and Triphenylsilyl (TPS) ether groups, and the like.
In the present invention, the above step (1), the steps from the compounds (7) to (13) to (8) are known in the art. And will be apparent to those skilled in the art based on the prior art.
The present invention also provides a process for preparing compound (9), which comprises the process for preparing compound (8) as above, and further converting compound (8) into compound (9),Wherein R 1 is as defined above.
Specifically, the method of the present invention for preparing compound (9) is as follows:
Step (1): removing hydroxyl protecting groups from the compound (7) to obtain an intermediate compound (13), converting the compound (13) into a compound (9) through a compound (8), and separating to obtain a product compound (9) and a byproduct mixture, wherein the byproduct mixture comprises one, two or three of the compounds (8 a), (8 b) and (8 c);
Step (II): the byproduct mixture is reconverted to compound (8) and compound (9) is obtained again from compound (8).
According to an embodiment of the present invention, the reaction formula for producing compound (9) from compound (7) via intermediate (13), compound (8), is shown below:
wherein R 1 is as defined above, PG is each independently selected from the same or different hydroxy protecting groups, preferably silyl hydroxy protecting groups, such as TMS, TES, TBS (TBDMS), TBDPS, TIPS, TPS.
The specific steps of the step (one) are as follows: the solution of compound (7) is reacted with a tetrabutylammonium fluoride solution in the presence of acetic acid. After a period of time, the alcoholic solution of calcium carbonate/acidic ion resin is added to continue the reaction. After the reaction is completed, the filtrate is filtered and concentrated, and the product compound (9) and the byproduct mixture are obtained through column chromatography.
In this method, the solution of the compound (7) is a tetrahydrofuran solution of the compound (7).
The tetrabutylammonium fluoride solution is a tetrahydrofuran solution of tetrabutylammonium fluoride.
The alcohol is selected from C 1-6 alkyl alcohols, preferably methanol, ethanol, isopropanol or a mixture thereof.
The acidic ion resin is Dowex 50WX8-400. The mass ratio of the acidic ion resin to the initiator compound (7) is 5:1 to 10:1, preferably 7:1 to 8:1.
The mass ratio of the calcium carbonate to the acidic ion resin is 1:2-1:5, preferably 1:3.
The filtration is performed through celite.
The reactions are all carried out at temperatures of from 10 to 40 ℃, preferably from 15 to 30 ℃.
The reaction of the solution of the compound (7) with a tetrabutylammonium fluoride solution in the presence of acetic acid is carried out for 20 to 60 hours. The alcoholic solution of calcium carbonate/acidic ion resin is added to continue the reaction for 10-30 hours.
The specific steps of the step (II) are as follows: the by-product mixture is dissolved in a mixed solvent of alcohol and water, and is converted into a compound (8) again in the presence of a base, the residue obtained by concentrating the reaction system is dissolved in an alcohol solvent, and an acidic ion resin is added to convert the compound (8) into a compound (9).
The step of reconverting the byproduct mixture to compound (8) according to an embodiment of the invention is described in detail hereinabove.
According to an embodiment of the present invention, in the step of converting the compound (8) into the compound (9),
The alcohol is selected from C 1-6 alkyl alcohols, preferably methanol, ethanol, isopropanol or a mixture thereof.
The acidic ion resin is Dowex 50WX8-400.
The mass ratio of the acidic ion resin to the initiator byproduct mixture is 1:1-5:1.
The reaction is completed at 10-40 c, preferably 15-30 c, for 2-5 hours.
The reaction also comprises the steps of filtering, washing, concentrating the filtrate and purifying by column chromatography to obtain the compound (9).
In the present invention, the recovered by-product compounds (8 a), (8 b) and/or (8 c) are converted into compound (8) by the method of the present invention as described hereinbefore, and compound (8) is converted into compound (9) again, thereby improving the conversion of compound (9).
In the present invention, methods for removing hydroxyl protecting groups are known to those skilled in the art, for example, using a hydroxyl protecting group remover, which refers to those reagents that react with a compound having a protected hydroxyl group to provide a compound having a deprotected hydroxyl group. The hydroxy protecting group remover and deprotection reaction conditions may be those known in the art. In one non-limiting example, the hydroxyl groups masked as silyl ethers may be unmasked by reaction with a fluoride source (e.g., a fluoride salt, such as KF or TBAF). Alternatively, the hydroxyl group protected as TMS or TES ether may be deprotected by reaction with a bronsted acid (e.g., carboxylic acid). In another non-limiting example, the hydroxyl group protected as an ester may be deprotected by reaction with a C 1-6 alkoxide (e.g., an alkali metal C 1-6 alkoxide or an alkaline earth metal C 1-6 alkoxide).
The invention also provides a method for preparing Ai Li Boolean, halichondrin B, which comprises the method for preparing the compound (8). Further, the above-mentioned process for producing the compound (9) is also included.
The beneficial effects are that:
The invention improves the method for preparing Ai Li Brin intermediate, recovers a large amount of by-products which are inevitably generated in the prior method in a simple and easy-to-operate way, and further converts the by-products into intermediate products, thereby improving the conversion rate of the reaction at the step and reducing the material cost of the whole synthesis process. The method has simple step operation, and the used solvent and other materials are easy to remove, thereby bringing great convenience to industrial production.
Detailed Description
The preparation method and application of the present invention will be described in further detail with reference to specific examples. It is to be understood that the following examples are illustrative only and are not to be construed as limiting the scope of the invention. All techniques implemented based on the above description of the invention are intended to be included within the scope of the invention. Unless otherwise indicated, the starting materials and reagents used in the following examples were either commercially available or may be prepared by known methods. Unless otherwise indicated, the starting materials and reagents used in the following examples were either commercially available or may be prepared by known methods. The experimental procedure, in which specific conditions are not noted in the examples, was performed according to conventional methods and conditions.
Example 1:
Tetrabutylammonium fluoride solution (123 mL,1M tetrahydrofuran solution) was taken, acetic acid (3.7 mL) was added, and the solution was stirred at room temperature for 10 minutes, and was labeled as solution A. Compound (7) (14.2 g) was dissolved in tetrahydrofuran (560 mL), and solution A was added thereto, and the reaction system was reacted at room temperature for 48 hours. Methanol (1.3L), calcium carbonate (34 g) and DOWEX 50WX8-400 (102.4 g) were added to the reaction system, and the reaction system was allowed to react at room temperature for 24 hours. The reaction system was filtered through celite, the filtrate was concentrated, and the compound (9) (6.54 g) was isolated by column chromatography in 83% yield; 2.08g of a crude compound (8 a), a compound (8 b) and a compound (8 c) were obtained.
Example 2: recovery of crude compound (8 a), compound (8 b), and compound (8 c) mixture
Crude compound (8 a), compound (8 b), compound (8 c) mixture (2.08 g) was dissolved in isopropanol (55 mL), concentrated ammonia water (55 mL) was added, and stirred overnight at 0 ℃, and the reaction solution was concentrated under reduced pressure as a spot plate monitoring that most of the mixture had been converted into compound (8); the concentrated residue was dissolved in methanol (120 mL), dowex 50WX8-400 (3.1 g) was added, and reacted at room temperature for 3 hours, and the spot plate was monitored that no compound (8) remained. The resulting mixture was filtered through celite, washed with methanol, and the filtrate was directly concentrated and then purified by column chromatography to give compound (9) (0.88 g).
Example 3: recovery of crude compound (8 a), compound (8 b), and compound (8 c) mixture
Dissolving crude compound (8 a), compound (8 b) and compound (8 c) mixture (2.0 g) in isopropanol (55 mL), adding concentrated ammonia water (55 mL), stirring at 10-20deg.C overnight, spot-plating to monitor that most of the mixture has been converted into compound (8), and concentrating the reaction solution under reduced pressure; the concentrated residue was dissolved in methanol (120 mL), dowex 50WX8-400 (3.0 g) was added, and reacted at room temperature for 3 hours, and the spot plate was monitored that no compound (8) remained. The resulting mixture was filtered through celite, washed with methanol, and the filtrate was directly concentrated and then purified by column chromatography to give compound (9) (0.8 g).
Example 4: recovery of crude compound (8 a), compound (8 b), and compound (8 c) mixture
Crude mixtures (2.0 g) of compound (8 a), compound (8 b) and compound (8 c) were dissolved in isopropanol (55 mL), concentrated aqueous ammonia (55 mL) was added, and stirred overnight at 30 ℃, and the reaction solution was concentrated under reduced pressure as monitored by dot plates that most of the mixture had been converted to compound (8); the concentrated residue was dissolved in methanol (120 mL), dowex 50WX8-400 (3.0 g) was added, and reacted at room temperature for 3 hours, and the spot plate was monitored that no compound (8) remained. The resulting mixture was filtered through celite, washed with methanol, and the filtrate was directly concentrated and then purified by column chromatography to give compound (9) (0.78 g).
The foregoing description of the specific embodiments of the present invention has been presented by way of example. The scope of the invention is not limited to the exemplary embodiments described above. Any modification, equivalent replacement, improvement, etc. made by those skilled in the art within the spirit and principle of the present invention should be included in the scope of protection of the claims of the present invention.
Claims (9)
1. A process for preparing compound (8), the process comprising:
(1) The compound (7) is converted into the compound (8) via the intermediate compound (13) as follows,
(2) Dissolving the by-product mixture produced from the above compounds (7) to (8) in a mixed solvent of alcohol and water, and reconverting into the compound (8) in the presence of a base, wherein the by-product mixture comprises one, two or three of the following compounds (8 a), (8 b) and (8 c),
Wherein R 1 is R OR, R is hydrogen, C 1-12 haloalkyl, C 1-12 alkyl optionally substituted with aryl, preferably, the C 1-12 haloalkyl, C 1-12 alkyl is preferably C 1-4 alkyl, the aryl substituted C 1-12 alkyl is phenyl substituted C 1-4 alkyl, such as benzyl, the PGs are each independently selected from the same OR different hydroxy protecting groups, preferably a silyl hydroxy protecting group, such as TMS, TES, TBS (TBDMS), TBDPS, TIPS, TPS.
2. The production process according to claim 1, wherein in the step (2), the base is selected from ammonia and amines. The amines are preferably: RNH 2,R2NH,R3 N, wherein R is C 1-6 alkyl.
In step (2), the alcohol is selected from C 1-6 alkyl alcohols, preferably methanol, ethanol, isopropanol or a mixture thereof.
3. The preparation method according to claim 1, wherein in step (2), the volume ratio of the alcohol to water is 1:2-2:1, preferably 1:1.
In step (2), the reaction is carried out at 0-50 ℃, preferably 0-30 ℃.
In step (2), the mass ratio of the base to the by-product mixture is from 1:1 to 1:8, preferably from 1:4 to 1:5..
4. The preparation process according to claim 1, wherein in step (2), the conversion time is 8 hours or more, preferably 12 to 24 hours.
In step (2), the reaction system is formed in the following manner: the byproduct mixture is dissolved in alcohol and then aqueous alkali is added.
5. A process for preparing compound (9), comprising the process for preparing compound (8) as claimed in any one of claims 1 to 4, and further converting compound (8) into compound (9),Wherein R 1, PG are as defined in claim 1.
6. The process according to claim 5, wherein the specific steps for preparing compound (9) are as follows:
Step (1): removing hydroxyl protecting groups from the compound (7) to obtain an intermediate compound (13), converting the compound (13) into a compound (9) through a compound (8), and separating to obtain a product compound (9) and a byproduct mixture, wherein the byproduct mixture comprises one, two or three of the compounds (8 a), (8 b) and (8 c);
Step (II): the byproduct mixture is reconverted to compound (8) and compound (9) is obtained again from compound (8).
7. The process of claim 6 wherein in step (one), the solution of compound (7) is reacted with a tetrabutylammonium fluoride solution in the presence of acetic acid. After a period of time, the alcoholic solution of calcium carbonate/acidic ion resin is added to continue the reaction. After the reaction is completed, the filtrate is filtered and concentrated, and the product compound (9) and the byproduct mixture are obtained through column chromatography.
In this method, the solution of the compound (7) is a tetrahydrofuran solution of the compound (7).
The tetrabutylammonium fluoride solution is a tetrahydrofuran solution of tetrabutylammonium fluoride.
The alcohol is selected from C 1-6 alkyl alcohols, preferably methanol, ethanol, isopropanol or a mixture thereof.
The acidic ion resin is Dowex 50WX8-400. The mass ratio of the acidic ion resin to the initiator compound (7) is 5:1 to 10:1, preferably 7:1 to 8:1.
The mass ratio of the calcium carbonate to the acidic ion resin is 1:2-1:5, preferably 1:3.
The filtration is performed through celite.
The reaction of the solution of the compound (7) with a tetrabutylammonium fluoride solution in the presence of acetic acid is carried out for 20 to 60 hours. The alcoholic solution of calcium carbonate/acidic ion resin is added to continue the reaction for 10-30 hours.
8. A process for producing according to claim 6,
The step (II) comprises the following steps: the by-product mixture is dissolved in a mixed solvent of alcohol and water, and is converted into a compound (8) again in the presence of a base, the residue obtained by concentrating the reaction system is dissolved in an alcohol solvent, and an acidic ion resin is added to convert the compound (8) into a compound (9).
The alcohol is selected from C 1-6 alkyl alcohols, preferably methanol, ethanol, isopropanol or a mixture thereof.
The acidic ion resin is Dowex 50WX8-400.
The mass ratio of the acidic ion resin to the initiator byproduct mixture is 1:1-5:1.
The reaction is completed at 10-40 c, preferably 15-30 c, for 2-5 hours.
9. A process for preparing Ai Li brin, halichondrin B, comprising the process for preparing compound (8) according to any one of claims 1-4, or comprising the process for preparing compound (9) according to any one of claims 5-8.
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