CN115368283A - Preparation method of cis-3-fluoro-4-hydroxypyrrolidine with chiral structure or achiral structure and derivatives thereof - Google Patents
Preparation method of cis-3-fluoro-4-hydroxypyrrolidine with chiral structure or achiral structure and derivatives thereof Download PDFInfo
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- CN115368283A CN115368283A CN202211124187.7A CN202211124187A CN115368283A CN 115368283 A CN115368283 A CN 115368283A CN 202211124187 A CN202211124187 A CN 202211124187A CN 115368283 A CN115368283 A CN 115368283A
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- hydroxypyrrolidine
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- 238000002360 preparation method Methods 0.000 title claims abstract description 23
- 238000000034 method Methods 0.000 claims abstract description 20
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims abstract description 8
- RCBGOJFTPHCJDB-QWWZWVQMSA-N (3r,4r)-4-fluoropyrrolidin-3-ol Chemical compound O[C@@H]1CNC[C@H]1F RCBGOJFTPHCJDB-QWWZWVQMSA-N 0.000 claims abstract description 7
- 239000000203 mixture Substances 0.000 claims abstract description 7
- 239000007800 oxidant agent Substances 0.000 claims description 19
- 150000001875 compounds Chemical class 0.000 claims description 18
- 229910052731 fluorine Inorganic materials 0.000 claims description 16
- -1 lithium aluminum hydride Chemical compound 0.000 claims description 16
- 230000001590 oxidative effect Effects 0.000 claims description 16
- 239000011737 fluorine Substances 0.000 claims description 14
- 125000001153 fluoro group Chemical group F* 0.000 claims description 13
- 125000000217 alkyl group Chemical group 0.000 claims description 8
- 125000003118 aryl group Chemical group 0.000 claims description 6
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 6
- 239000003638 chemical reducing agent Substances 0.000 claims description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 6
- 238000007254 oxidation reaction Methods 0.000 claims description 6
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 4
- UORVGPXVDQYIDP-UHFFFAOYSA-N borane Chemical compound B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 claims description 4
- 150000002148 esters Chemical class 0.000 claims description 4
- 229910052740 iodine Inorganic materials 0.000 claims description 4
- 239000011630 iodine Substances 0.000 claims description 4
- 239000003960 organic solvent Substances 0.000 claims description 4
- 230000003647 oxidation Effects 0.000 claims description 4
- 239000002798 polar solvent Substances 0.000 claims description 4
- 238000006722 reduction reaction Methods 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 4
- 238000006646 Dess-Martin oxidation reaction Methods 0.000 claims description 3
- NKLCNNUWBJBICK-UHFFFAOYSA-N dess–martin periodinane Chemical group C1=CC=C2I(OC(=O)C)(OC(C)=O)(OC(C)=O)OC(=O)C2=C1 NKLCNNUWBJBICK-UHFFFAOYSA-N 0.000 claims description 3
- 239000001257 hydrogen Substances 0.000 claims description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims description 3
- 239000012279 sodium borohydride Substances 0.000 claims description 3
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 3
- 125000001424 substituent group Chemical group 0.000 claims description 3
- 239000000758 substrate Substances 0.000 claims description 3
- 239000012448 Lithium borohydride Substances 0.000 claims description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 2
- 150000001298 alcohols Chemical class 0.000 claims description 2
- 125000003545 alkoxy group Chemical group 0.000 claims description 2
- 229910000085 borane Inorganic materials 0.000 claims description 2
- 239000007810 chemical reaction solvent Substances 0.000 claims description 2
- 239000004210 ether based solvent Substances 0.000 claims description 2
- 150000002170 ethers Chemical class 0.000 claims description 2
- CJXGPJZUDUOZDX-UHFFFAOYSA-N fluoromethanone Chemical group F[C]=O CJXGPJZUDUOZDX-UHFFFAOYSA-N 0.000 claims description 2
- 150000008282 halocarbons Chemical class 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 2
- QWPPOHNGKGFGJK-UHFFFAOYSA-N hypochlorous acid Chemical compound ClO QWPPOHNGKGFGJK-UHFFFAOYSA-N 0.000 claims description 2
- 239000012280 lithium aluminium hydride Substances 0.000 claims description 2
- 229910052700 potassium Inorganic materials 0.000 claims description 2
- 239000011591 potassium Substances 0.000 claims description 2
- 150000003839 salts Chemical class 0.000 claims description 2
- 238000006243 chemical reaction Methods 0.000 abstract description 23
- 238000004519 manufacturing process Methods 0.000 abstract description 4
- 239000002994 raw material Substances 0.000 abstract description 3
- 239000012535 impurity Substances 0.000 abstract description 2
- 238000000746 purification Methods 0.000 abstract description 2
- 239000000047 product Substances 0.000 description 23
- 239000003814 drug Substances 0.000 description 16
- 229940079593 drug Drugs 0.000 description 16
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 14
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- 239000000243 solution Substances 0.000 description 10
- 239000012043 crude product Substances 0.000 description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 5
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 4
- 239000002547 new drug Substances 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 238000011161 development Methods 0.000 description 2
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- 239000000543 intermediate Substances 0.000 description 2
- 229930014626 natural product Natural products 0.000 description 2
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 2
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 2
- 238000010791 quenching Methods 0.000 description 2
- 230000000171 quenching effect Effects 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- KTBDFQPHEPDHQW-RQJHMYQMSA-N tert-butyl (3r,4s)-3-fluoro-4-hydroxypyrrolidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1C[C@H](O)[C@H](F)C1 KTBDFQPHEPDHQW-RQJHMYQMSA-N 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- OTWVFHZMWFGHSJ-UHFFFAOYSA-N 1-fluoropyrrolidine Chemical compound FN1CCCC1 OTWVFHZMWFGHSJ-UHFFFAOYSA-N 0.000 description 1
- RCBGOJFTPHCJDB-UHFFFAOYSA-N 4-fluoropyrrolidin-3-ol Chemical group OC1CNCC1F RCBGOJFTPHCJDB-UHFFFAOYSA-N 0.000 description 1
- ZFIOCUITTUUVPV-MEDUHNTESA-N 7-[(3s,4s)-3-[(cyclopropylamino)methyl]-4-fluoropyrrolidin-1-yl]-6-fluoro-1-(2-fluoroethyl)-8-methoxy-4-oxoquinoline-3-carboxylic acid Chemical compound C([C@@H]1[C@H](F)CN(C1)C1=C(C2=C(C(C(C(O)=O)=CN2CCF)=O)C=C1F)OC)NC1CC1 ZFIOCUITTUUVPV-MEDUHNTESA-N 0.000 description 1
- 229910014033 C-OH Inorganic materials 0.000 description 1
- 208000035473 Communicable disease Diseases 0.000 description 1
- 229910014570 C—OH Inorganic materials 0.000 description 1
- 206010024971 Lower respiratory tract infections Diseases 0.000 description 1
- 238000006751 Mitsunobu reaction Methods 0.000 description 1
- 235000009827 Prunus armeniaca Nutrition 0.000 description 1
- 244000018633 Prunus armeniaca Species 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 1
- FKCMADOPPWWGNZ-YUMQZZPRSA-N [(2r)-1-[(2s)-2-amino-3-methylbutanoyl]pyrrolidin-2-yl]boronic acid Chemical compound CC(C)[C@H](N)C(=O)N1CCC[C@H]1B(O)O FKCMADOPPWWGNZ-YUMQZZPRSA-N 0.000 description 1
- ZVQOOHYFBIDMTQ-UHFFFAOYSA-N [methyl(oxido){1-[6-(trifluoromethyl)pyridin-3-yl]ethyl}-lambda(6)-sulfanylidene]cyanamide Chemical compound N#CN=S(C)(=O)C(C)C1=CC=C(C(F)(F)F)N=C1 ZVQOOHYFBIDMTQ-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 229940124307 fluoroquinolone Drugs 0.000 description 1
- 231100000025 genetic toxicology Toxicity 0.000 description 1
- 230000001738 genotoxic effect Effects 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 239000002198 insoluble material Substances 0.000 description 1
- 239000008932 jinhong Substances 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 229950006602 lascufloxacin Drugs 0.000 description 1
- 150000002611 lead compounds Chemical class 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000013332 literature search Methods 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 244000052769 pathogen Species 0.000 description 1
- 150000003235 pyrrolidines Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 238000004064 recycling Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000012827 research and development 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
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- QOWQDMIPYOKNHP-UHFFFAOYSA-N triphenoxy phosphate Chemical compound C=1C=CC=CC=1OOP(OOC=1C=CC=CC=1)(=O)OOC1=CC=CC=C1 QOWQDMIPYOKNHP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/12—Oxygen or sulfur atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/24—Oxygen or sulfur atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pyrrole Compounds (AREA)
Abstract
The invention discloses a preparation method of cis-3-fluoro-4-hydroxypyrrolidine with a chiral structure or an achiral structure shown in formula (I) and derivatives thereof, which is characterized in that cis-trans mixture with the chiral structure or the achiral structure or trans-3-fluoro-4-hydroxypyrrolidine and derivatives thereof are oxidized into carbonyl or dihydroxy, and the carbonyl or dihydroxy is further reduced to generate the cis-3-fluoro-4-hydroxypyrrolidine derivatives with the chiral structure or the achiral structure. The method has the advantages of good yield, less treatment and purification impurities, controllability, direct application in the next reaction, simplified operation, more environment friendliness in the preparation process, and mass production of the pharmaceutical raw material.
Description
Technical Field
The invention relates to the field of preparation of fluorine-containing pyrrolidine structures, and particularly relates to a preparation method of cis-3-fluoro-4-hydroxypyrrolidine and derivatives thereof with chiral structures or achiral structures.
Background
Fluorine atoms play a crucial role in the development of new drugs, and after fluorine atoms or fluorine-containing groups are introduced into a molecular structure, because fluorine is the element with the strongest electronegativity, the fluorine often provides the required hydrogen bond effect in the action process of drug molecules and biological targets, so that the combination degree of the drug molecules and the targets is improved, and the activity of the drugs is improved; because the strong fluorocarbon bond causes the difficulty of breaking the fluorocarbon bond, the introduction of fluorine atoms into drug molecules can often improve the metabolic stability of the drug; the strong electron withdrawing effect of fluorine atoms changes the distribution of electron density in molecules, influences the acid-base property of compounds, further changes the activity and bioavailability of drug molecules, and the introduction of fluorine atoms can change the fat solubility of the drug molecules and further influence the absorption of the drug molecules in human bodies; in addition, the introduction of fluorine atoms can change the selective recognition of drug molecules to targets; the conformation of the molecule can also be altered, etc.
Therefore, the introduction of fluorine atoms into drug molecules is a powerful means in the development of new drugs. (see "Fluoropharmaceuticals", xiao Ji Chang, lu Shoufu, lin Jinhong, chemical Press, publication time: 2022, 04/01/month; CIP approval No. 2021257632 ISBN 978-7-122-40413-8).
The nitrogen-containing heterocyclic compound is widely existed in natural products and artificially synthesized drug molecules, and shows high biological activity.
The pyrrolidine derivative is a common specific structural unit in natural products and drug molecules, which draws wide attention of chemists, and how to develop a simple, efficient and strong-universality method to construct the compound is always a goal pursued by organic chemists.
The pyrrolidine structure is a very important intermediate in the research and development of new drugs, and the structure is contained in a plurality of drugs. And introducing fluorine atoms and fluorine-containing groups into pyrrolidine molecules is a new strategy for developing new drugs.
An antibacterial structure as shown by the following structural formula as synthesized by apricot lin, japan in 2019: lacofloxacin (Lascufloxacin) represented by formula 1 is an effective orally active fluoroquinolone antibacterial agent, can effectively inhibit infection caused by various pathogens, and can be used for research of various infectious diseases including lower respiratory tract infection.
The synthesized fluorine substituted pyrrolidine structure, especially chiral products obtained by a chemical method, also has very wide application in drug molecules.
Through literature search, a large number of drugs and lead compounds thereof described in the patent contain a fluorinated pyrrole structure. However, the existing methods for synthesizing the fluoropyrrolidine are few, and have the problems of complicated routes, poor substrate compatibility, harsh conditions and the like.
The preparation method in the prior art is generally to prepare cis by inverting the structure of trans form through Mitsunobu reaction by the method shown in the following chemical formula 2. However, the method has strict requirements, more byproducts are generated, particularly, the produced triphenoxyphosphate has genotoxicity and poor atom economy, partial byproducts are difficult to completely remove, the product is difficult to purify, and large-scale preparation and production are difficult to realize.
It is therefore desirable to design new processes suitable for large-scale production.
Disclosure of Invention
In order to overcome the defects in the prior art, the invention aims to provide a preparation method of cis-3-fluoro-4-hydroxypyrrolidine and derivatives thereof with chiral structures or achiral structures and products thereof.
The method has mild reaction conditions, convenient operation, lower cost and good yield, is suitable for preparing the cis-3-fluoro-4-hydroxypyrrolidine and the derivatives thereof with chiral structures or non-chiral structures, and is suitable for industrialized mass production.
The preparation principle on which the invention is based is as follows:
due to the characteristics of fluorine atoms, in the ortho-fluorine hydroxyl structure compound, the C-F bond and the C-OH bond are in a cis structure and are more thermally stable (J.Med.chem.2018, 61, 5822-5880), so when the hydroxyl is reduced from carbonyl, the product tends to generate a cis-form thermodynamically stable product.
In order to realize the purpose of the invention, the adopted technical scheme is as follows:
a method for preparing cis-3-fluoro-4-hydroxypyrrolidine and its derivatives with chiral or achiral structures comprises the following steps:
starting from a cis-trans mixture with a chiral structure or an achiral structure shown as a structural formula (II) or trans-3-fluoro-4-hydroxypyrrolidine and derivatives thereof;
obtaining a fluorine carbonyl or dihydroxy compound with a chiral structure or an achiral structure shown as a structural formula (III) through oxidation to carbonyl or dihydroxy;
further reducing to generate cis-3-fluoro-4-hydroxypyrrolidine with a chiral structure or an achiral structure shown as a structural formula (I) and derivatives thereof;
in a preferred embodiment of the present invention, the preparation method specifically comprises the following steps:
step one, an oxidation step:
the cis-trans mixture with chiral structure or achiral structure shown in the structural formula (II) or the trans-3-fluoro-4-hydroxypyrrolidine and the derivatives thereof and an oxidant are subjected to oxidation reaction under the solvent condition of-78 ℃ to 100 ℃ to generate the fluorocarbonyl or dihydroxy compound with chiral structure or achiral structure shown in the structural formula (III),
the feeding ratio of the substrate (II) to the oxidant is 1:1.0-5.0 equivalent;
the oxidant is any one or more of hypochlorous acid and salt oxidant thereof, high-valence iodine oxidant and Swern oxidant;
the reaction solvent is any one or more of water, esters, halogenated hydrocarbons and ether solvents;
step two, a reduction step:
in an organic solvent, under the action of a reducing agent, a fluorine carbonyl or a dihydroxy compound with a chiral structure or an achiral structure shown in a structural formula (III) undergoes a reduction reaction at 0-150 ℃ to obtain cis-3-fluoro-4-hydroxypyrrolidine with a chiral structure or an achiral structure shown in a structural formula (I) and a derivative thereof;
the organic solvent is a strong polar solvent;
the reducing agent is any one or more of sodium borohydride, lithium borohydride, potassium borohydride, borane solution, lithium aluminum hydride or lithium tri-sec-butylborohydride;
the using equivalent of the reducing agent is 0.25-5.0 equivalent relative to the fluorine carbonyl or dihydroxy compound with chiral structure or achiral structure shown in the structural formula (III).
In a preferred embodiment of the invention, the higher iodine oxidizer is any one or more of Dess-Martin oxidizer or IBX oxidizer.
In a preferred embodiment of the present invention, the strongly polar solvent is any one or more of water, alcohols, esters, and ethers.
In a preferred embodiment of the invention, the compound shown in the formula (II) is trans-3-fluoro-4-hydroxypyrrolidine and derivatives thereof, and the preparation method is adopted to obtain the cis-3-fluoro-4-hydroxypyrrolidine and derivatives thereof with chiral structures, wherein the stereoselectivity of the fluorine atom position is maintained, and the stereoselectivity of the hydroxyl position is completely reversed.
A cis-3-fluoro-4-hydroxypyrrolidine with a chiral structure or an achiral structure shown in formula (I) and derivatives thereof, which are products of the preparation method;
wherein R is hydrogen, C 1 -C 9 Alkyl, aryl, benzyl, CF 3 CO、R 2 CO or R 3 Any one or more of OCO;
R 2 is C 1 -C 9 Any one or more of alkyl, aryl or benzyl,
R 3 is C 1 -C 9 Any one or more of alkyl, aryl or benzyl;
the R group is optionally unsubstituted or substituted with one or more substituents selected from the group consisting of alkyl, hydroxyalkyl, alkoxy, and hydroxy.
Compared with the prior art, the invention has the beneficial effects that:
first, the present invention provides a novel method for the synthesis of racemic or chiral cis 3-fluoro-4-hydroxypyrrolidine structures, and provides the preparation of corresponding optically pure products;
secondly, reagents used in each step of reaction are cheap and easy to obtain, the technical scheme of the synthetic reaction is reasonable, and the post-treatment and purification are convenient;
thirdly, the invention has wide applicability to raw material structures and can be chiral or achiral; can be pure trans or cis-trans mixture. More importantly, the mixture left after the product obtained by the scheme is purified can be re-oxidized and re-reduced for recycling.
Fourthly, the reaction in each step of the method has high yield, less processed and purified impurities and controllable property, can be directly used for the next reaction, simplifies the operation, ensures that the preparation process is more environment-friendly, and can be produced in large quantities to meet the production of pharmaceutical raw material medicines.
Detailed Description
The following examples are given to aid in the understanding of the invention, but are not intended to limit the scope of the invention. In particular, the synthesis of chiral compounds in the examples is understood to be the opposite configuration of intermediates and products, and is within the scope of this patent.
Unless otherwise stated, substituents and groups are as defined in formula (I).
The present invention is further illustrated below by reference to specific examples, which are intended to be illustrative only and not to limit the scope of the invention. The experimental procedures, in which specific conditions are not noted in the following examples, are generally carried out under conventional conditions or conditions recommended by the manufacturers. Proportions and percentages are by weight unless otherwise indicated.
The preparation principle on which the invention is based is as follows:
due to the characteristics of fluorine atoms, in the compound with an ortho-fluorine hydroxyl structure, a C-F bond and a C-O bond are in a cis structure and are more stable thermally, so that when the carbonyl is reduced into the hydroxyl, the product tends to generate a cis thermodynamically stable product.
Example 1:
preparation of N-Cbz-3-fluoro-4-carbonylpyrrolidine (V)
DMSO (32.8g, 0.42mol, 2.0eq) is dissolved in anhydrous dichloromethane (300 mL) under the protection of nitrogen, the temperature of a reaction system is reduced to-78 ℃, a dichloromethane solution (100 mL) of oxalyl chloride (53.3g, 0.42mol, 2.0eq) is dropwise added into the reaction system, and the temperature is ensured not to exceed-65 ℃ in the dropwise adding process. Subsequently, a solution of the compound represented by the formula (IV) (50g, 0.21mol,1.0 eq) in methylene chloride (100 mL) was added at low temperature.
After stirring was continued for 30 minutes after completion of the dropwise addition, triethylamine (106g, 1.05mol,5.0 eq) was added. The reaction was slowly warmed to room temperature and the reaction was complete as detected by TLC. The reaction solution was quenched with aqueous sodium bisulfite solution, the organic phase was collected by liquid separation, and the aqueous phase was extracted with methylene dichloride and combined. The resulting organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated at low temperature to give a carbonyl product represented by formula (V) as a yellow solid (53.5 g, crude product) which was used directly in the next reaction.
The data for the carbonyl product of formula (V) are as follows:
1 HNMR(400MHz,CDCl 3 δ (ppm): 7.43-7.312 (m, 5H), 5.32 (s, 2H), 5.10 (td, J =7.6hz,51.2hz, 1h), 4.39-4.30 (m, 1H), 4.06-3.92 (m, 2H), 3.79-3.68 (m, 1H); MS-ESI theoretical value (M): 237.1; actual values: 256.1 (M + H) 2 O+H + )。
Example 2:
preparation of cis-N-Cbz-3-fluoro-4-hydroxypyrrolidine (VI)
The compound represented by the formula (V) (50g, 210mmol, 1.0eq) was dissolved in a mixed solution of tetrahydrofuran (100 mL) and methanol (100 mL), and after the reaction solution was cooled to 0 to 5 ℃, sodium borohydride solid (4.8g, 130mmol, 0.6eq) was added gradually in portions. The reaction solution slowly returns to room temperature and is continuously stirred until the reaction is completed. Adding saturated ammonium chloride into the reaction solution for quenching, extracting for three times by ethyl acetate, combining organic phases, drying and concentrating to obtain a crude compound product with cis as the main component shown in the formula (VI), wherein the crude compound product is yellow solid.
Crystallization from n-hexane/ethyl acetate =5:1 gave the product as a white solid (32.5g, 136mmol, 65% yield, 95% purity).
The data for the product are as follows:
1 HNMR(400MHz,CDCl 3 δ (ppm): 7.40-7.33 (m, 5H), 5.18 (s, 2H), 5.03 (d, J =50.8hz, 1h), 4.39-4.27 (m, 1H), 3.90-3.78 (m, 2H), 3.67 (ddd, J =4.4hz,13.6hz,33.6hz, 1h), 3.33 (q, J =10.8hz, 1h), 2.72 (brs, 1H); MS-ESI theoretical value (M): 239.2; actual values: 240.3 (M + H) + )。
Example 3:
preparation of (R) -N-Boc-3-fluoro-4-carbonylpyrrolidine (VIII)
The starting material (20g, 97.5mmol, 1.0eq) represented by the formula (VII) was dissolved in anhydrous dichloromethane (200 mL), and after the reaction solution was cooled to 0 to 5 ℃, dess-Martin oxidant (49.6 g,117mmol, 1.2eq) was added in portions. The resulting white suspension was stirred for 2 hours and the reaction was detected to be complete. The reaction was filtered through a small section of silica gel to remove most of the white insoluble material. The obtained filtrate was concentrated at low temperature to remove most of the solvent, and the crude product (VIII) was directly subjected to the next reaction.
Example 4:
preparation of (3R, 4S) -N-Boc-3-fluoro-4-hydroxypyrrolidine (IX)
The crude product (VIII) prepared in the above step was placed in a mixed solvent of tetrahydrofuran (150 mL) and methanol (150 mL) and NaBH (OAc) was added slowly at 0-5 deg.C 3 (24.8g, 117mmol, 1.2eq). The reaction solution slowly returns to room temperature and is continuously stirred for 12 hours to detect the reaction is complete. And (3) quenching the reaction by adding saturated ammonium chloride, extracting with ethyl acetate for three times, combining organic phases, drying and concentrating to obtain a crude product shown in the formula (IX). The crude product was crystallized twice in n-hexane/ethyl acetate =6:1 solvent to give the desired product as white crystals (16.1g, 78.4mmol, yield 67%, purity 98%).
The data for the product are as follows:
1 HNMR(400MHz,CDCl 3 δ (ppm): 5.02 (d, J =54.0hz, 1h), 4.34-4.29 (m, 1H), 3.81-3.53 (m, 3H), 3.24 (q, J =9.6hz, 1h), 2.65 (brs, 1H); MS-ESI theoretical value (M): 205.1; actual values: 206.1 (M + H) + )。
Example 5:
preparation of (3S, 4R) -N-Fmoc-3-fluoro-4-hydroxypyrrolidine (X)
Prepared under the same conditions as in example 4 using crude product (VIII) to afford product (X) as a white solid (yield 63%, purity 98%).
Data for product (X) are as follows:
1 HNMR(400MHz,CDCl 3 δ (ppm): 7.79 (d, J =7.2hz, 2h), 7.61 (t, J =7.2hz, 2h), 7.43 (t, J =7.6hz, 2h), 7.34 (t, J =7.6hz, 2h), 5.05 (d, J =54hz, 1h), 4.50-4.35 (M, 3H), 4.26 (t, J =6.8hz, 1h), 4.93-3.56 (M, 3H), 3.32 (q, J =9.2hz, 1h), 2.44 (brs, 1H), MS-ESI: theoretical value (M): 327.4; actual values: 328.4 (M + H) + )。
Example 6:
preparation of (3R, 4S) -N-benzyl-3-fluoro-4-hydroxypyrrolidine (XI)
The crude product (VIII) was prepared in the same manner as in example 4 to give the product of the formula (XI) as a white solid (yield 70%, purity 97%).
The data for the product of formula (XI) are as follows:
1 HNMR(400MHz,CDCl 3 δ (ppm): 7.40-7.28 (M, 5H), 5.01 (dtd, 2.8Hz,5.6Hz,55.2Hz, 1H), 4.35-4.26 (M, 1H), 3.70 (dd, 3.6Hz,16.8Hz, 1H), 3.12-2.81 (M, 4H), 2.65 (td, J =2.4Hz,6.4Hz, 1H), MS-ESI theoretical value (M): 239.2; actual values: 240.3 (M + H) + )。
Claims (6)
1. A method for preparing cis-3-fluoro-4-hydroxypyrrolidine and its derivatives with chiral or achiral structures is characterized by comprising the following steps:
starting from a cis-trans mixture with a chiral structure or an achiral structure shown as a structural formula (II) or trans-3-fluoro-4-hydroxypyrrolidine and derivatives thereof;
obtaining a fluorine carbonyl or dihydroxy compound with a chiral structure or an achiral structure shown as a structural formula (III) through oxidation to carbonyl or dihydroxy;
further reducing to generate cis-3-fluoro-4-hydroxypyrrolidine with a chiral structure or an achiral structure shown as a structural formula (I) and derivatives thereof;
2. the method for preparing cis-3-fluoro-4-hydroxypyrrolidine and its derivatives with chiral or achiral structure according to claim 1, wherein the method comprises the following steps:
step one, an oxidation step:
the cis-trans mixture with chiral structure or achiral structure shown in the structural formula (II) or the trans-3-fluoro-4-hydroxypyrrolidine and the derivatives thereof and an oxidant are subjected to oxidation reaction under the solvent condition of-78 ℃ to 100 ℃ to generate the fluorocarbonyl or dihydroxy compound with chiral structure or achiral structure shown in the structural formula (III),
the feeding ratio of the substrate (II) to the oxidant is 1:1.0-5.0 equivalent;
the oxidant is any one or more of hypochlorous acid and salt oxidant thereof, high-valence iodine oxidant and Swern oxidant;
the reaction solvent is any one or more of water, esters, halogenated hydrocarbons and ether solvents;
step two, a reduction step:
in an organic solvent, under the action of a reducing agent, a fluorine carbonyl or a dihydroxy compound with a chiral structure or an achiral structure shown in a structural formula (III) undergoes a reduction reaction at 0-150 ℃ to obtain cis-3-fluoro-4-hydroxypyrrolidine with a chiral structure or an achiral structure shown in a structural formula (I) and a derivative thereof;
the organic solvent is a strong polar solvent;
the reducing agent is any one or more of sodium borohydride, lithium borohydride, potassium borohydride, borane solution, lithium aluminum hydride or lithium tri-sec-butylborohydride;
the using equivalent of the reducing agent is 0.25 to 5.0 equivalents relative to the fluorine carbonyl or dihydroxy compound with chiral structure or achiral structure shown in the structural formula (III).
3. The method for preparing cis-3-fluoro-4-hydroxypyrrolidine and its derivatives with chiral or achiral structure according to claim 2, wherein the iodine-rich oxidant is Dess-Martin oxidant or IBX oxidant.
4. The method for preparing cis-3-fluoro-4-hydroxypyrrolidine with chiral or achiral structure and its derivatives according to claim 2, wherein the highly polar solvent is one or more of water, alcohols, esters, and ethers.
5. The method for preparing cis-3-fluoro-4-hydroxypyrrolidine and its derivatives with chiral or achiral structure according to claim 2, wherein the compound represented by formula (II) is trans-3-fluoro-4-hydroxypyrrolidine and its derivatives, and the method can be used to obtain cis-3-fluoro-4-hydroxypyrrolidine and its derivatives with chiral structure with stereoselectivity of fluorine atom position and stereoselectivity of hydroxyl position completely reversed.
6. A cis-3-fluoro-4-hydroxypyrrolidine with a chiral structure or an achiral structure as shown in formula (I) and derivatives thereof, which are the products of the preparation method according to any one of claims 1 to 5;
wherein R is hydrogen, C 1 -C 9 Alkyl, aryl, benzyl, CF 3 CO、R 2 CO or R 3 Any one or more of OCO;
R 2 is C 1 -C 9 Any one or more of alkyl, aryl or benzyl,
R 3 is C 1 -C 9 Any one or more of alkyl, aryl or benzyl;
the R group is optionally unsubstituted or substituted with one or more substituents selected from the group consisting of alkyl, hydroxyalkyl, alkoxy, and hydroxy.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101094846A (en) * | 2004-10-18 | 2007-12-26 | 伊莱利利公司 | 1-(hetero)aryl-3-amino-pyrollidine derivatives for use as mglur3 receptor antagonists |
| CN103038212A (en) * | 2010-05-31 | 2013-04-10 | 杏林制药株式会社 | Process for preparation of 3-substituted-4-fluoropyrrolidine derivatives |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101094846A (en) * | 2004-10-18 | 2007-12-26 | 伊莱利利公司 | 1-(hetero)aryl-3-amino-pyrollidine derivatives for use as mglur3 receptor antagonists |
| CN103038212A (en) * | 2010-05-31 | 2013-04-10 | 杏林制药株式会社 | Process for preparation of 3-substituted-4-fluoropyrrolidine derivatives |
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| ANDREA TESTA等: "3-Fluoro-4-hydroxyprolines: Synthesis, conformational analysis, and stereoselective recognition by the VHL E3 Ubiquitin ligase for targeted protein degradation", JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, vol. 140, no. 29, 27 June 2018 (2018-06-27), pages 9299 - 9313, XP055758524, DOI: 10.1021/jacs.8b05807 * |
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| SUO CHEN等: "Diastereoselective synthesis and conformational analysis of 4, 5-difluoropipecolic acids", ORGANIC & BIOMOLECULAR CHEMISTRY, vol. 18, no. 40, 1 October 2020 (2020-10-01), pages 8192 - 8198 * |
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