CN114634515A - Stereoselective synthesis method of (3aS,6aR) -lactone - Google Patents
Stereoselective synthesis method of (3aS,6aR) -lactone Download PDFInfo
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- CN114634515A CN114634515A CN202210179962.2A CN202210179962A CN114634515A CN 114634515 A CN114634515 A CN 114634515A CN 202210179962 A CN202210179962 A CN 202210179962A CN 114634515 A CN114634515 A CN 114634515A
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- Prior art keywords
- reaction
- lactone
- formula
- hydrogen
- borohydride
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- 230000000707 stereoselective effect Effects 0.000 title claims abstract description 14
- 238000001308 synthesis method Methods 0.000 title claims abstract description 7
- 238000006243 chemical reaction Methods 0.000 claims abstract description 106
- -1 cyclic anhydride Chemical class 0.000 claims abstract description 103
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- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims abstract description 33
- 150000003839 salts Chemical class 0.000 claims abstract description 33
- 238000000034 method Methods 0.000 claims abstract description 17
- 229910000000 metal hydroxide Inorganic materials 0.000 claims abstract description 14
- 150000004692 metal hydroxides Chemical class 0.000 claims abstract description 14
- 239000003960 organic solvent Substances 0.000 claims abstract description 14
- 239000002253 acid Substances 0.000 claims abstract description 10
- 150000007530 organic bases Chemical class 0.000 claims abstract description 10
- 238000006722 reduction reaction Methods 0.000 claims abstract description 10
- 229910052500 inorganic mineral Inorganic materials 0.000 claims abstract description 7
- 238000007363 ring formation reaction Methods 0.000 claims abstract description 7
- 238000000354 decomposition reaction Methods 0.000 claims abstract description 6
- 238000006555 catalytic reaction Methods 0.000 claims abstract description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 68
- 239000001257 hydrogen Substances 0.000 claims description 68
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 50
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 45
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 37
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 26
- 229960004063 propylene glycol Drugs 0.000 claims description 23
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 20
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- 239000007864 aqueous solution Substances 0.000 claims description 12
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 10
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims description 10
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- 125000005809 3,4,5-trimethoxyphenyl group Chemical group [H]C1=C(OC([H])([H])[H])C(OC([H])([H])[H])=C(OC([H])([H])[H])C([H])=C1* 0.000 claims description 8
- 125000003762 3,4-dimethoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C(OC([H])([H])[H])C([H])=C1* 0.000 claims description 8
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 7
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- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 6
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 6
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- 229910052784 alkaline earth metal Inorganic materials 0.000 claims description 6
- 125000003545 alkoxy group Chemical group 0.000 claims description 6
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 6
- 229910052794 bromium Inorganic materials 0.000 claims description 6
- 239000000460 chlorine Substances 0.000 claims description 6
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- 229910052731 fluorine Inorganic materials 0.000 claims description 6
- 239000011737 fluorine Substances 0.000 claims description 6
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 claims description 6
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- 239000012448 Lithium borohydride Substances 0.000 claims description 5
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 4
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- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 4
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims description 4
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- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 4
- 229910052783 alkali metal Inorganic materials 0.000 claims description 4
- 150000001340 alkali metals Chemical class 0.000 claims description 4
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 claims description 4
- QARVLSVVCXYDNA-UHFFFAOYSA-N bromobenzene Chemical compound BrC1=CC=CC=C1 QARVLSVVCXYDNA-UHFFFAOYSA-N 0.000 claims description 4
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 4
- 125000002541 furyl group Chemical group 0.000 claims description 4
- 239000012046 mixed solvent Substances 0.000 claims description 4
- 239000000203 mixture Substances 0.000 claims description 4
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- 125000001544 thienyl group Chemical group 0.000 claims description 4
- DNIAPMSPPWPWGF-VKHMYHEASA-N (+)-propylene glycol Chemical compound C[C@H](O)CO DNIAPMSPPWPWGF-VKHMYHEASA-N 0.000 claims description 3
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims description 3
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 3
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 3
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 3
- 229910052791 calcium Inorganic materials 0.000 claims description 3
- 239000011575 calcium Substances 0.000 claims description 3
- XTAZYLNFDRKIHJ-UHFFFAOYSA-N n,n-dioctyloctan-1-amine Chemical compound CCCCCCCCN(CCCCCCCC)CCCCCCCC XTAZYLNFDRKIHJ-UHFFFAOYSA-N 0.000 claims description 3
- 229910017604 nitric acid Inorganic materials 0.000 claims description 3
- 229910052700 potassium Inorganic materials 0.000 claims description 3
- 239000011591 potassium Substances 0.000 claims description 3
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 3
- 239000012279 sodium borohydride Substances 0.000 claims description 3
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 claims description 3
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 2
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- IIFFFBSAXDNJHX-UHFFFAOYSA-N 2-methyl-n,n-bis(2-methylpropyl)propan-1-amine Chemical compound CC(C)CN(CC(C)C)CC(C)C IIFFFBSAXDNJHX-UHFFFAOYSA-N 0.000 claims description 2
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 2
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 2
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- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 claims description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N hexane Substances CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 2
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- CLZGJKHEVKJLLS-UHFFFAOYSA-N n,n-diheptylheptan-1-amine Chemical compound CCCCCCCN(CCCCCCC)CCCCCCC CLZGJKHEVKJLLS-UHFFFAOYSA-N 0.000 claims description 2
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- 238000010596 desymmetrization reaction Methods 0.000 description 1
- 229960002179 ephedrine Drugs 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- WJRBRSLFGCUECM-UHFFFAOYSA-N hydantoin Chemical compound O=C1CNC(=O)N1 WJRBRSLFGCUECM-UHFFFAOYSA-N 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 150000002596 lactones Chemical class 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000000636 p-nitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)[N+]([O-])=O 0.000 description 1
- KWGRBVOPPLSCSI-WCBMZHEXSA-N pseudoephedrine Chemical compound CN[C@@H](C)[C@@H](O)C1=CC=CC=C1 KWGRBVOPPLSCSI-WCBMZHEXSA-N 0.000 description 1
- 229960003908 pseudoephedrine Drugs 0.000 description 1
- 238000007142 ring opening reaction Methods 0.000 description 1
- 238000013341 scale-up Methods 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 150000003333 secondary alcohols Chemical class 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
- C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
- C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention belongs to the technical field of organic chemistry, and particularly relates to a stereoselective synthesis method of (3aS,6aR) -lactone. The method comprises the steps of carrying out a desymmetry reaction on cyclic anhydride and a chiral auxiliary agent propylene glycol in a first organic solvent in the presence of an organic base, carrying out a double decomposition reaction on the cyclic anhydride and a water solution of a metal hydroxide to convert the cyclic anhydride and the water solution of the metal hydroxide into a dicarboxylic acid monoester salt, carrying out a reduction reaction on the dicarboxylic acid monoester salt and borohydride in a second organic solvent, and carrying out a ring closure reaction under the catalysis of inorganic mineral acid to obtain (3aS,6aR) -lactone; overall yield of product>88%, percent enantiomeric excess: (eeValue)>99 percent. The method has the advantages of cheap and easily obtained raw materials, mild reaction conditions, simple and convenient operation, high product yield and high optical purity, and has good industrial application prospect.
Description
Technical Field
The invention belongs to the technical field of organic chemistry, and particularly relates to a synthetic method of (3aS,6aR) -lactone.
Background
The (3aS,6aR) -lactone is a key intermediate for synthesizing d-Biotin (d-Biotin, vitamin H and coenzyme R). The structural formula is shown as the following formula (I):
in the formula, R1Hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, phenyl, p-tolyl, p-methoxyphenyl, 3, 4-dimethylphenyl, 3, 4-dimethoxyphenyl, 3,4, 5-trimethylphenyl, 3,4, 5-trimethoxyphenyl or p-chlorophenyl, etc., and Ar is phenyl, p-tolyl, p-methoxyphenyl, 3, 4-dimethylphenyl, 3, 4-dimethoxyphenyl, 3,4, 5-trimethylphenyl, 3,4, 5-trimethoxyphenyl, p-chlorophenyl, thienyl, furyl or naphthyl, etc.
Gerecke et al (Helv. Chim. acta.,1970,53, 991-one 999) monoesterify cis-1, 3-dibenzylimidazoline-2-ketone-2H-furo [3,4] imidazole-2, 4, 6-trione (cyclic anhydride II) with cyclohexanol to give racemic cyclohexanehexo-cyclic acid monocyclohexyl ester, then subject it to diastereomeric crystallization with pseudoephedrine to give (4S,5R) -half-ester, which is then reduced with lithium borohydride and ring-closed to give (3aS,6aR) -lactone (I). German patent 2058243, European patent 92194, Chinese patent 106365 and Chenfen et al (Proc. Natl. Acad. Chem.Sci.En., Proc. higher school, 2001,22, 1141) describe the preparation of (3aS,6aR) -lactone (I) by resolution of racemic cyclic acid monoester with dehydroabietylamine, substituted chiral diphenylethylamine and (1S,2S) -threo-1- (p-nitrophenyl) -1, 3-propanediol to give (4S,5R) -half-ester, followed by borohydride reduction and ring closure. The resolution method has the problems of low single resolution yield, complex operation, low efficiency, high cost and the like.
Gerecke et al (Helv. Chim. acta.,1970,53, 991-one 999), European patent 92194, European patent 44158, world patent 2004094367 and Chinese patent 109748924 describe the preparation of (4S,5R) -half-esters by diastereoselective esterification of cyclic anhydrides with cholesterol, substituted chiral secondary alcohols/tert-butanol, (S) -N-methyl-. alpha. -phenylethylamine, (S) -1,1, -diphenyl-1, 2-propanediol and 1,1, -dinaphthyl-1, 2-propanediol as chiral auxiliaries, followed by reduction and ring closure to give the desired compounds (I), respectively. US6884893 discloses a process for preparing (4S,5R) -cyclic acid half-ester by diastereoselective ring-opening reaction of cyclic anhydride with ephedrine amino alcohol derivatives, and obtaining lactone (I) by reduction and ring closure, wherein the total yield of the process is 86%, and the enantiomeric excess percentage (ee) can reach 99%. The chiral auxiliary used in the methods has the defects of high price, difficult preparation, inconvenient recovery, high cost and the like.
Chinese patents 1473832, 101157655 and 101284832 respectively disclose methods for preparing (4S,5R) -half-ester by asymmetric alcoholysis of cyclic anhydride using chiral amine (1S,2S) -1- (p-nitrophenyl) -2-N, N-dimethylamino-3-triphenylmethoxy-1-propanol, 9-propargyl quinine and thiourea quinine as catalysts. European patent 84892 and Chen Feng et al (adv. Synth. Catal.,2005,347,549-. These methods all have the disadvantages of complicated operation, low enantioselectivity, high cost and difficult industrial scale-up.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provide a stereoselective synthesis method of (3aS,6aR) -lactone (I), which is simple, high in yield, high in optical purity and low in cost.
The invention provides a stereoselective synthesis method of (3aS,6aR) -lactone (I), which comprises the following synthetic route:
in the formula, R1Hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, phenyl, p-tolyl, p-methoxyphenyl, 3, 4-dimethylphenyl, 3, 4-dimethoxyphenyl, 3,4, 5-trimethylphenyl, 3,4, 5-trimethoxyphenyl, p-chlorophenyl and the like, Ar is phenyl, p-tolyl, p-methoxyphenyl, 3, 4-dimethylphenyl, 3, 4-dimethoxyphenyl, 3,4, 5-trimethylphenyl, 3,4, 5-trimethoxyphenyl, p-chlorophenyl, thienyl, furyl, naphthyl or the like;
R2is hydrogen, fluorine, chlorine, bromine, iodine, C1-C6Alkyl radical, C3-C6Cycloalkyl or C1-C6An alkoxy group; r3Is hydrogen, fluorine, chlorine, bromine, iodine, C1-C6Alkyl radical, C3-C6Cycloalkyl or C1-C6Alkoxy, M is an alkali or alkaline earth metal cation;
the synthesis method comprises the following specific steps:
step (1): the cyclic anhydride (II) and chiral auxiliary propylene glycol (III) are subjected to a de-symmetrization reaction in a first organic solvent in the presence of an organic base, and then subjected to a double decomposition reaction with an aqueous solution of metal hydroxide to be converted into a dicarboxylic acid monoester salt (IV);
step (2): carrying out reduction reaction on the dicarboxylic acid monoester salt (IV) prepared in the step (1) and borohydride in a second organic solvent, and then carrying out ring closure reaction under the catalysis of inorganic mineral acid to prepare (3aS,6aR) -lactone (I);
the structural formula of the cyclic anhydride (II) is as follows:
in the formula, R1Hydrogen, C1-C6 alkyl, phenyl, p-tolyl, p-methoxyphenyl, 3, 4-dimethylphenyl, 3, 4-dimethoxyphenyl, 3,4, 5-trimethylphenyl, 3,4, 5-trimethoxyphenyl or p-chlorophenyl, Ar is phenyl, p-tolyl, p-methoxyphenyl, 3, 4-dimethylphenyl, 3, 4-dimethoxyphenyl, 3,4, 5-trimethylphenyl, 3,4, 5-trimethoxyphenyl, p-chlorophenyl, thienyl, furyl or naphthyl, etc.;
the propylene glycol (III) is (S) -1,2 propylene glycol, and the structural formula is as follows:
in the formula, R2Is hydrogen, fluorine, chlorine, bromine, iodine, C1-C6Alkyl radical, C3-C6Cycloalkyl or C1-C6An alkoxy group; r3Is hydrogen, fluorine, chlorine, bromine, iodine, C1-C6Alkyl radical, C3-C6Cycloalkyl or C1-C6An alkoxy group.
The structural formula of the target product (3aS,6aR) -lactone (I) is aS follows:
in the formula, R1And Ar is as above.
In the step (1), the chiral auxiliary propylene glycol (III) is any one of (S) -1,2 propylene glycols, which has a high diastereoselectivity reaction effect, mild reaction conditions, simple and convenient operation, high chemical yield and high optical purity, and the chiral propylene glycol is convenient to synthesize, wide in raw material source and convenient to recover.
In the step (1), the organic base is an organic tertiary amine selected from one of triethylamine, tripropylamine, triisobutylamine, tri-n-butylamine, tripentylamine, trihexylamine, triheptylamine, trioctylamine, 1, 4-diazabicyclo [2.2.2] octane (DABCO), 4-dimethylaminopyridine, 1, 8-diazabicycloundec-7-ene (DBU), or a mixture of a plurality of the foregoing.
Preferably, in the step (1), the organic base is tri-n-butylamine, which is widely available and low in cost.
In the step (1), the first organic solvent is one selected from benzene, toluene, xylene, anisole, fluorobenzene, chlorobenzene, bromobenzene, dichloromethane, chloroform, 1, 2-dichloroethane, tetrahydrofuran, 1, 4-dioxane, ethylene glycol dimethyl ether, diethyl ether, N-hexane, cyclohexane, acetonitrile, acetone, N-dimethylformamide, N-dimethylacetamide, dimethyl sulfoxide, N-methylpyrrolidone, sulfolane, 1, 3-dimethyl-2-imidazolidinone, hexamethylphosphoric triamide, N-alkylpyridinium salt, 1, 3-dialkylimidazolium salt, or a mixed solvent of a plurality thereof; preferably, in the step (1), the first organic solvent is toluene or p-xylene, which has the advantages of optimal effect, wide source and convenient recovery.
In the step (1), in the de-symmetrization reaction, the molar ratio of the cyclic anhydride (II), the chiral auxiliary propylene glycol (III) and the organic base is controlled within the range of 1 (0.8-1.5) to (0.1-2.0), and the reaction can be smoothly completed.
Preferably, in the step (1), the molar ratio of the cyclic anhydride (II), the chiral auxiliary propylene glycol (III) and the organic base is 1 (1.05-1.3) to (0.11-1.5), which is the best material ratio, so that the materials are saved, and the reaction can be completed smoothly.
In the step (1), the temperature of the de-symmetrization reaction is controlled within the range of-20 to 80 ℃, and the reaction can be smoothly completed.
Preferably, in the step (1), the temperature of the de-symmetrization reaction is controlled within the range of-15 to 60 ℃, the reaction effect is good, and the energy consumption is lower.
In the step (1), the reaction time of the de-symmetrization is controlled within the range of 2-48 hours, and the reaction can be smoothly completed.
In the step (1), the metal hydroxide is alkali metal hydroxide or alkaline earth metal hydroxide, and is selected from one of lithium hydroxide, sodium hydroxide, potassium hydroxide, magnesium hydroxide, calcium hydroxide and barium hydroxide, or a mixture of a plurality of the above.
Preferably, the metal hydroxide in step (1) is lithium hydroxide, so that the reaction effect is better, and the optical purity of the product is higher.
In the step (1), the feeding amount of the metal hydroxide in the double decomposition reaction is controlled so that the molar ratio of the metal hydroxide to the cyclic anhydride (II) is (1-1.8): 1.
Preferably, in the step (1), the feeding amount of the metal hydroxide in the double decomposition reaction is controlled to enable the molar ratio of the metal hydroxide to the cyclic anhydride (II) to be (1.1-1.5): 1, so that materials are saved, and the reaction can be smoothly completed.
In step (1), the dicarboxylic acid monoester salt (IV) comprises two diastereomers (IV a) and (IV b):
in the formula, R1、Ar、R2And R3As above, M is an alkali metal or alkaline earth metal cation.
In the step (2), the second organic solvent is one of tetrahydrofuran, 2-methyltetrahydrofuran, 1, 4-dioxane, methanol, ethanol, isopropanol and ethylene glycol, or a mixed solvent of a plurality of the solvents.
Preferably, the second organic solvent in step (2) is tetrahydrofuran, which is widely available and has low cost.
In the step (2), the borohydride is selected from any one of lithium borohydride, sodium borohydride, potassium borohydride and calcium borohydride.
Preferably, in step (2), the borohydride is lithium borohydride, which is chemically stable and is cheap and easily available.
In the step (2), the molar ratio of the dicarboxylic acid monoester salt (IV) to the borohydride is controlled within the range of 1 (1-4), and the reaction can be smoothly completed.
Preferably, the molar ratio of the dicarboxylic acid monoester salt (IV) to the borohydride in the step (2) is 1 (1.02-2.5), so that the material is saved, and the reaction can be smoothly completed.
In the step (2), the temperature of the reduction reaction is controlled within the range of 0-100 ℃, and the reaction can be smoothly completed.
Preferably, in the step (2), the reduction reaction temperature is 0-80 ℃, the reaction effect is better, and the energy consumption is lower.
In the step (2), the inorganic mineral acid is selected from any one of hydrochloric acid, sulfuric acid, nitric acid and phosphoric acid.
Preferably, in the step (2), the inorganic mineral acid is hydrochloric acid, so that the reaction effect is better.
In the step (2), the temperature of the ring closing reaction is controlled within the range of 20-150 ℃, and the reaction can be smoothly completed.
Preferably, in the step (2), the ring closing reaction temperature is 30-120 ℃, the reaction effect is better, and the energy consumption is lower.
According to the technical scheme, cyclic anhydride (II) and chiral auxiliary propylene glycol (III) are subjected to a desymmetrization reaction in a first organic solvent in the presence of organic base, then subjected to a double decomposition reaction with an aqueous solution of metal hydroxide to be converted into dicarboxylic acid monoester salt (IV), and then subjected to a reduction reaction with borohydride in a second organic solvent, and then subjected to a ring closure reaction under the catalysis of inorganic mineral acid to prepare the (3aS,6aR) -lactone (I).
The synthetic route of the technical scheme is as follows:
in the formula, R1、Ar、R2And R3As above, M is an alkali metal or alkaline earth metal cation.
Detailed Description
In order to explain technical contents, structural features, and objects and effects of the technical means in detail, the following detailed description is given with reference to specific embodiments. The present embodiment is implemented on the premise of the technical solution of the present invention, and a detailed implementation manner and a specific operation process are given, but the scope of the present invention is not limited to the following embodiments.
In the present invention, the term "C1-C6 alkyl" denotes a straight or branched chain alkyl group having 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, and the like.
In the present invention, examples of the term "C3-C6 cycloalkyl" include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
In the present invention, the term "C1-C6 alkoxy group" means a straight-chain or branched alkoxy group having 1 to 6 carbon atoms, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentoxy, n-hexoxy, and the like.
Example 1
(4S,5R) -1, 3-dibenzyl-5- ((((((S) -1, 1-bis ([1,1' -diphenyl group)]-4-yl) -1-hydroxypropane-2-yl)) oxy) preparation of lithium (IV) carbonyl) -2-oxoimidazolidine-4-carboxylate the substrate, cyclic anhydride (II) (R in formula II)1Ar is hydrogen, Ar is phenyl, which is collectively known as cis-1, 3-dibenzylimidazolin-2-one-2H-furo [3,4-d ]]Imidazole-2, 4, 6-trione) (33.6g, 0.10mol), chiral auxiliary (S) -1, 1-bis ([1,1' -biphenyl)]-4-yl) -1, 2-propanediol (III) (formula III R2Is hydrogen, R3Hydrogen) (39.9g, 0.105moL) and anhydrous toluene (200ml) were placed in a dry reaction flask, freshly distilled n-butylamine (23.90ml,0.10moL) was added dropwise to the reaction flask at 0 ℃ after completion of the addition, the reaction flask was stirred at 25 ℃ for 8h, after completion of the reaction, 115ml of a 1moL/L aqueous lithium hydroxide solution (5.04g, 0.12moL) was added to the reaction flask at room temperature, stirring was continued at room temperature for 2.5h, the reaction solution was filtered and the residue was washed with 100ml of water and dried under vacuum to give a white powder, i.e. the monoester salt of dicarboxylic acid (IV) (R in formula IV)1Is hydrogen, Ar is phenyl, R2Is hydrogen, R3M is hydrogen, lithium cation, 69.3g, 96%, 100% de).
Characterization of compound (IV) in this example: m.p. 225-]D 25＝-22.3(c 1.0,DMF)；1H NMR(400MHz,DMSO)δ7.67–7.57(m,12H),7.45–7.42(m,4H),7.37–7.20(m,6H),7.17(d,J＝6.8Hz,2H),7.10–7.12(m,2H),6.80(d,J＝6.4Hz,2H),6.04(q,J＝6.2Hz,1H),6.00(s,1H),4.75(d,J＝16.4Hz,1H),4.67(d,J＝16.4Hz,1H),4.30(d,J＝15.2Hz,1H),3.77(d,J＝9.6Hz,1H),3.69(d,J＝9.6Hz,1H),3.44(d,J＝15.2Hz,1H),1.16(d,J＝6.2Hz,3H)；HRMS m/z:[M+H]+calcd for C46H40LiN2O6 723.3042,found 723.3063.
Example 2
Preparation of lithium (IV) (4S,5R) -1, 3-dibenzyl-5- ((((((S) -1, 1-bis (4 '-methyl- [1,1' -biphenyl ] -4-yl) -1-hydroxypropan-2-yl)) oxy) carbonyl) -2-oxoimidazolidine-4-carboxylate
Reacting the substrate cyclic anhydride (II) (R in formula II)1Ar is hydrogen, Ar is phenyl, which is collectively known as cis-1, 3-dibenzylimidazolin-2-one-2H-furo [3,4-d ]]Imidazole-2, 4, 6-trione) (33.6g, 0.10mol), chiral auxiliary (S) -1, 1-bis (4 '-methyl- [1,1' -biphenyl)]-4-yl) -1, 2-propanediol (III) (of formula IIIR2Is hydrogen, R34' -methyl) (42.8g, 0.10mol) and anhydrous toluene (200ml) are placed in a dry reaction bottle, newly distilled n-butylamine (23.90ml,0.10mol) is dripped into the reaction bottle at 0 ℃, after dripping is finished, the reaction bottle is placed at 25 ℃ and stirred for 10h, after the reaction is finished, 115ml of 1mol/L lithium hydroxide aqueous solution (5.04g, 0.12mol) is added into the reaction bottle at room temperature, stirring is continued at room temperature for 2.5h, then the reaction liquid is filtered, the filter residue is washed by 100ml of water, and drying in vacuum is carried out to obtain white powder, namely dicarboxylic acid monoester salt (IV) (R in formula IV)1Is hydrogen, Ar is phenyl, R2Is hydrogen, R34' -methyl, M is lithium cation, 69.8g, 93%, 100% de).
Example 3
Preparation of lithium (IV) (4S,5R) -1, 3-dibenzyl-5- ((((((S) -1, 1-bis (4 '-fluoro- [1,1' -biphenyl ] -4-yl) -1-hydroxypropan-2-yl)) oxy) carbonyl) -2-oxoimidazolidine-4-carboxylate
Reacting the substrate cyclic anhydride (II) (R in formula II)1Ar is hydrogen, Ar is phenyl, which is collectively known as cis-1, 3-dibenzylimidazolin-2-one-2H-furo [3,4-d ]]Imidazole-2, 4, 6-trione) (33.6g, 0.10mol), chiral auxiliary (S) -1, 1-bis (4 '-fluoro- [1,1' -biphenyl)]-4-yl) -1, 2-propanediol (III) (formula III R2Is hydrogen, R34' -fluoro) (43.7g, 0.105mol) and anhydrous toluene (240ml) are placed in a dry reaction bottle, newly distilled n-butylamine (23.90ml,0.10mol) is dripped into the reaction bottle at 0 ℃, after dripping is finished, the reaction bottle is placed at 25 ℃ and stirred for 8h, after the reaction is finished, 115ml of 1mol/L lithium hydroxide aqueous solution (5.04g, 0.12mol) is added into the reaction bottle at room temperature, stirring is continued for 2.5h at room temperature, then the reaction liquid is filtered, the filter residue is washed by 100ml of water, and drying in vacuum is carried out to obtain white powder, namely dicarboxylic acid monoester salt (IV) (hydrogen in formula IV, Ar is phenyl, R is phenyl, and R is monoester salt (IV)2Is hydrogen, R3Is 4' -fluoro, M is lithium cation, 70.5g, 93%, 98.6% de).
Example 4
Preparation of lithium (IV) 4-oxoimidazolidine-4-carboxylate (4S,5R) -1, 3-dibenzyl-5- ((((((S) -1, 1-bis ([1,1' -biphenyl ] -4-yl) -1-hydroxypropan-2-yl)) oxy) carbonyl)
Reacting the substrate cyclic anhydride (II) (formula I)In I, R1Ar is hydrogen, Ar is phenyl, which is collectively known as cis-1, 3-dibenzylimidazolin-2-one-2H-furo [3,4-d ]]Imidazole-2, 4, 6-trione) (33.6g, 0.10mol), chiral auxiliary (S) -1, 1-bis ([1,1' -biphenyl)]-4-yl) -1, 2-propanediol (III) (formula III R2Is hydrogen, R3Hydrogen) (39.9g, 0.105mol) and anhydrous p-xylene (200ml) are placed in a dry reaction flask, newly distilled tri-n-octylamine (5.1ml,0.012mol) is dripped into the reaction flask at 0 ℃, after dripping is finished, the reaction flask is placed at 25 ℃ and stirred for 12h, after the reaction is finished, 115ml of 1mol/L lithium hydroxide aqueous solution (5.04g, 0.12mol) is added into the reaction flask at room temperature, stirring is continued for 2.5h at room temperature, then the reaction solution is filtered, the filter residue is washed by 100ml of water, and vacuum drying is carried out to obtain white powder, namely the dicarboxylic acid monoester salt (IV) (R in formula IV)1Is hydrogen, Ar is phenyl, R2Is hydrogen, R3M is hydrogen, lithium cation, 68.5g, 95%, 100% de).
Example 5
Preparation of lithium (IV) 4-oxoimidazolidine-4-carboxylate (4S,5R) -1, 3-dibenzyl-5- ((((((S) -1, 1-bis ([1,1' -biphenyl ] -4-yl) -1-hydroxypropan-2-yl)) oxy) carbonyl)
Reacting the substrate cyclic anhydride (II) (R in formula II)1Ar is hydrogen, Ar is phenyl, which is collectively known as cis-1, 3-dibenzylimidazolin-2-one-2H-furo [3,4-d ]]Imidazole-2, 4, 6-trione) (33.6g, 0.10mol), chiral auxiliary (S) -1, 1-bis ([1,1' -biphenyl)]-4-yl) -1, 2-propanediol (III) (formula III R2Is hydrogen, R3Hydrogen) (38.0g, 0.10mol) and anhydrous p-xylene (200ml) were placed in a dry reaction flask, freshly distilled 1, 8-diazabicycloundec-7-ene (14.95ml,0.10mol) was added dropwise to the reaction flask at 0 ℃ after completion of the addition, the reaction flask was stirred at 25 ℃ for 18h, after completion of the reaction, 115ml of a 1mol/L aqueous lithium hydroxide solution (5.04g, 0.12mol) was added to the reaction flask at room temperature, stirring was continued at room temperature for 3h, the reaction solution was filtered and the residue was washed with 100ml of water and dried under vacuum to give a white powder which was the dicarboxylic acid monoester salt (IV) (R in formula IV)1Is hydrogen, Ar is phenyl, R2Is hydrogen, R3M is a lithium cation, 68.3g, 95%, 98.8% de) for hydrogen.
Example 6
Preparation of lithium (IV) (4S,5R) -1, 3-dibenzyl-5- ((((((S) -1, 1-bis (4 '-chloro- [1,1' -biphenyl ] -4-yl) -1-hydroxypropan-2-yl)) oxy) carbonyl) -2-oxoimidazolidine-4-carboxylate
Reacting the substrate cyclic anhydride (II) (R in formula II)1Ar is hydrogen, Ar is phenyl, which is collectively known as cis-1, 3-dibenzylimidazolin-2-one-2H-furo [3,4-d ]]Imidazole-2, 4, 6-trione) (33.6g, 0.10mol), chiral auxiliary (S) -1, 1-bis (4 '-chloro- [1,1' -biphenyl)]-4-yl) -1, 2-propanediol (III) (formula III R2Is hydrogen, R34' -chloro) (47g, 0.105mol) and anhydrous p-xylene (200ml) are placed in a dry reaction bottle, freshly distilled n-butylamine (23.90ml,0.10mol) is dropped into the reaction bottle, the reaction bottle is stirred for 10h at 25 ℃, after the reaction is finished, 115ml of 1mol/L lithium hydroxide aqueous solution (5.04g, 0.12mol) is added into the reaction bottle at room temperature, the stirring is continued for 3h at room temperature, then the reaction solution is filtered, the filter residue is washed with 100ml of water, and the white powder, namely the dicarboxylic acid monoester salt (IV) (R in formula IV) is obtained by vacuum drying1Is hydrogen, Ar is phenyl, R2Is hydrogen, R3Is 4' -chloro, M is lithium cation, 72.6g, 92%, 100% de).
Example 7
Preparation of lithium (IV) (4S,5R) -1, 3-dibenzyl-5- ((((((S) -1, 1-bis (4 '-methoxy- [1,1' -biphenyl ] -4-yl) -1-hydroxypropan-2-yl)) oxy) carbonyl) -2-oxoimidazolidine-4-carboxylate
Reacting the substrate cyclic anhydride (II) (R in formula II)1Ar is hydrogen, Ar is phenyl, which is collectively known as cis-1, 3-dibenzylimidazolin-2-one-2H-furo [3,4-d ]]Imidazole-2, 4, 6-trione) (33.6g, 0.10mol), chiral auxiliary (S) -1, 1-bis (4 '-methoxy- [1,1' -biphenyl)]-4-yl) -1, 2-propanediol (III) (formula III R2Is hydrogen, R34' -methoxy) (46.2g, 0.105mol) and anhydrous toluene (200ml) were placed in a dry reaction flask, freshly distilled n-butylamine (23.90ml,0.10mol) was added dropwise to the reaction flask, the reaction flask was stirred at 25 ℃ for 16h, after completion of the reaction, 115ml of a 1mol/L aqueous lithium hydroxide solution (5.04g, 0.12mol) was added to the reaction flask at room temperature, stirring was continued at room temperature for 3h, the reaction solution was filtered and the filter residue was washed with 100ml of water, and the residue was washed with water and driedDrying in air to obtain white powder, i.e. dicarboxylic acid monoester salt (IV) (R in formula IV)1Is hydrogen, Ar is phenyl, R2Is hydrogen, R3Is 4' -methoxy, M is lithium cation, 72.0g, 92%, 100% de).
Example 8
Preparation of lithium (IV) (4S,5R) -1, 3-dibenzyl-5- ((((((S) -1, 1-bis (4 '-propyl- [1,1' -biphenyl ] -4-yl) -1-hydroxypropan-2-yl)) oxy) carbonyl) -2-oxoimidazolidine-4-carboxylate
Reacting the substrate cyclic anhydride (II) (R in formula II)1Ar is hydrogen, Ar is phenyl, which is collectively known as cis-1, 3-dibenzylimidazolin-2-one-2H-furo [3,4-d ]]Imidazole-2, 4, 6-trione) (33.6g, 0.10mol), chiral auxiliary (S) -1, 1-bis (4 '-n-propyl- [1,1' -biphenyl)]-4-yl) -1, 2-propanediol (III) (formula III R2Is hydrogen, R34' -n-propyl) (48.6g, 0.105mol) and anhydrous toluene (220ml) are placed in a dry reaction bottle, newly distilled n-butylamine (23.90ml,0.10mol) is dripped into the reaction bottle, the reaction bottle is stirred for 18h at 25 ℃, after the reaction is finished, 115ml of 1mol/L lithium hydroxide aqueous solution (5.04g, 0.12mol) is added into the reaction bottle at room temperature, the stirring is continued for 3h at room temperature, then the reaction solution is filtered, the filter residue is washed by 100ml of water, and the white powder, namely the dicarboxylic acid monoester salt (IV) (R in formula IV) is obtained after the reaction is finished, the white powder is the dicarboxylic acid monoester salt (IV)1Is hydrogen, Ar is phenyl, R2Is hydrogen, R3Is 4' -n-propyl, M is lithium cation, 74g, 92%, 100% de).
Example 9
Preparation of lithium (IV) 4-oxoimidazolidine-4-carboxylate (4S,5R) -1, 3-dibenzyl-5- (((((S) -1, 1-bis (2-cyclopropane-4 '-n-butoxy- [1,1' -biphenyl ] -4-yl) -1-hydroxypropan-2-yl)) oxy) carbonyl)
Reacting the substrate cyclic anhydride (II) (R in formula II)1Ar is hydrogen, Ar is phenyl, which is collectively known as cis-1, 3-dibenzylimidazolin-2-one-2H-furo [3,4-d ]]Imidazole-2, 4, 6-trione) (33.6g, 0.10mol), chiral auxiliary agent (S) -1, 1-di (2-cyclopropane-4 '-n-butoxy- [1,1' -biphenyl-4-yl)]) -1, 2-propanediol (III) (formula III wherein R22-cyclopropane, R34' -n-butoxy) (66.53g, 0.11mol) and dry toluene (200ml) were placed in a dry reaction flask,dripping freshly distilled n-butylamine (23.90ml,0.10mol) into a reaction bottle at 0 ℃, after dripping, placing the reaction bottle at 25 ℃ for stirring for 10h, after the reaction is finished, adding 115ml of 1mol/L lithium hydroxide aqueous solution (5.04g, 0.12mol) into the reaction bottle at room temperature, continuing stirring for 3h at room temperature, then filtering the reaction solution, washing filter residue with 100ml of water, and drying in vacuum to obtain white powder, namely the dicarboxylic acid monoester salt (IV) (R in formula IV)1Is hydrogen, Ar is phenyl, R22-cyclopropane, R34' -n-butoxy group, M is lithium cation, 87.6g, 92.5%, 98.6% de).
Example 10
Preparation of lithium (IV) 4-oxoimidazolidine-4-carboxylate (4S,5R) -1, 3-dibenzyl-5- ((((((S) -1, 1-bis (4 '-methyl- [1,1' -biphenyl ] -4-yl) -1-hydroxypropan-2-yl)) oxy) carbonyl)
Reacting the substrate cyclic anhydride (II) (R in formula II)1Ar is hydrogen, Ar is phenyl, which is collectively known as cis-1, 3-dibenzylimidazolin-2-one-2H-furo [3,4-d ]]Imidazole-2, 4, 6-trione) (33.6g, 0.10mol), chiral auxiliary (S) -1, 1-bis (4 '-methyl- [1,1' -biphenyl)]-4-yl) -1, 2-propanediol (III) (formula III R2Is hydrogen, R34' -methyl) (42.8g, 0.10mol) and anhydrous p-xylene (200ml) are placed in a dry reaction bottle, newly distilled n-butylamine (23.90ml,0.10mol) is dripped into the reaction bottle at 0 ℃, after dripping is finished, the reaction bottle is placed at 25 ℃ and stirred for 14h, after the reaction is finished, 115ml of 1mol/L lithium hydroxide aqueous solution (5.04g, 0.12mol) is added into the reaction bottle at room temperature, stirring is continued for 2.5h at room temperature, then the reaction solution is filtered, the filter residue is washed by 100ml of water, and drying in vacuum is carried out to obtain white powder, namely the dicarboxylic acid monoester salt (IV) (R in formula IV)1Is hydrogen, Ar is phenyl, R2Is hydrogen, R3Is 4' -methyl, M is lithium cation, 69.8g, 93%, 100% de).
Example 11
Preparation of lithium (IV) (4S,5R) -1, 3-dibenzyl-5- ((((((S) -1, 1-bis (4 '-fluoro- [1,1' -biphenyl ] -4-yl) -1-hydroxypropan-2-yl)) oxy) carbonyl) -2-oxoimidazolidine-4-carboxylate
Reacting the substrate cyclic anhydride (II) (R in formula II)1Is hydrogen, Ar is phenyl, which is fully known as cis-1, 3-diBenzylindmidazolin-2-one-2H-furo [3,4-d]Imidazole-2, 4, 6-trione) (33.6g, 0.10mol), chiral auxiliary (S) -1, 1-bis (4 '-fluoro- [1,1' -biphenyl)]-4-yl) -1, 2-propanediol (III) (formula III R2Is hydrogen, R34' -fluoro) (43.7g, 0.105mol) and anhydrous p-xylene (200ml) are placed in a dry reaction bottle, newly distilled n-butylamine (23.90ml,0.10mol) is dripped into the reaction bottle at 0 ℃, after dripping is finished, the reaction bottle is placed at 25 ℃ and stirred for 18h, after the reaction is finished, 115ml of 1mol/L lithium hydroxide aqueous solution (5.04g, 0.12mol) is added into the reaction bottle at room temperature, stirring is continued for 2.5h at room temperature, then the reaction solution is filtered, the filter residue is washed by 100ml of water, and drying in vacuum is carried out to obtain white powder, namely the dicarboxylic acid monoester salt (IV) (R in formula IV)1Is hydrogen, Ar is phenyl, R2Is hydrogen, R3Is 4' -fluoro, M is lithium cation, 69.7g, 92%, 100% de).
Example 12
Preparation of lithium (4S,5R) -1, 3-dibenzyl-5- ((((((S) -1, 1-bis (3-n-butyl-4 '-cyclohexyl- [1,1' -biphenyl ] -4-yl) -1-hydroxypropan-2-yl)) oxy) carbonyl) -2-oxoimidazolidine-4-carboxylate (IV)
Reacting the substrate cyclic anhydride (II) (R in formula II)1Ar is hydrogen, Ar is phenyl, which is collectively known as cis-1, 3-dibenzylimidazolin-2-one-2H-furo [3,4-d ]]Imidazole-2, 4, 6-trione) (33.6g, 0.10mol), chiral auxiliary agent (S) -1, 1-di (3-n-butyl-4 '-cyclohexyl- [1,1' -biphenyl]-4-yl) -1, 2-propanediol (III) (formula III R2Is 3-n-butyl, R34' -cyclohexyl) (72.3g, 0.11mol) and anhydrous p-xylene (200ml) are placed in a dry reaction bottle, newly distilled n-butylamine (23.90ml,0.10mol) is dripped into the reaction bottle at 0 ℃, after dripping is finished, the reaction bottle is placed at 25 ℃ and stirred for 24h, after the reaction is finished, 115ml of 1mol/L lithium hydroxide aqueous solution (5.04g, 0.12mol) is added into the reaction bottle at room temperature, stirring is continued for 2.5h at room temperature, then the reaction solution is filtered, the filter residue is washed by 100ml of water, and drying in vacuum is carried out to obtain white powder, namely the dicarboxylic acid monoester salt (IV) (R in formula IV)1Is hydrogen, Ar is phenyl, R2Is 3-n-butyl, R3Is 4' -cyclohexyl, M is lithium cation, 92.7g, 92.8%, 100% de).
Example 13
Preparation of (3aS,6aR) -1, 3-dibenzyl-tetrahydro-4H-furo [3,4-d ] imidazole-2, 4(1H) -dione (I)
Placing a newly prepared tetrahydrofuran solution (42mmol, 42mL) of lithium borohydride in a dry reaction bottle, dropwise adding a solution of IV (compound IV prepared in example 1, 20g, 28mmol) dissolved in 60mL of anhydrous tetrahydrofuran at 0 ℃ under stirring, after the dropwise addition, moving to room temperature to react for 6h, after the reaction is finished, adding 100mL of water and 100mL of toluene, stirring at room temperature for 30min, extracting the aqueous phase with toluene three times (50mL × 3) after phase separation, combining the organic phases, washing the combined organic phases with water twice (50mL × 2), combining the aqueous phases, concentrating the combined aqueous phase under reduced pressure, adding 60mL of 2mol/L hydrochloric acid, stirring at 75 ℃ for 1h, performing suction filtration, washing with 50mL of water, and performing vacuum drying on a filter cake to obtain a white crystalline powder, namely the target product (3aS,6aR) -lactone (I) (R in formula I)1Hydrogen, Ar phenyl) (8.6g, 95%).
Characterization of compound (I) in this example: m.p.195-196 ℃; [ alpha ] to]25 D＝+60.5(c 2.0,CHCl3)；1H NMR(400MHz,CDCl3)δ7.50–7.23(m,10H),5.05(d,J＝14.8Hz,1H),4.64(d,J＝15.2Hz,1H),4.38(dd,J＝15.2,10.4Hz,2H),4.24–4.08(m,3H),3.94(d,J＝8.6Hz,1H)；HRMS[M+Na]+calcd for C19H18N2NaO3 345.1210,found 345.1211.
Example 14
Preparation of (3aS,6aR) -1, 3-dibenzyl-tetrahydro-4H-furo [3,4-d ] imidazole-2, 4(1H) -dione (I)
Placing newly prepared tetrahydrofuran solution (70mmol,40mL) of sodium borohydride in a dry reaction bottle, dropwise adding solution of IV (IV prepared in example 1, 20g, 28mmol) dissolved in 60mL anhydrous tetrahydrofuran at 0 ℃ under stirring, after dropwise adding, moving to room temperature to react for 12h, after finishing the reaction, adding 100mL water and 100mL toluene, stirring at room temperature for 30min, extracting the aqueous phase with toluene three times (50mL x 3) after phase separation, combining the organic phases, washing the combined organic phases with water twice (50mL x 2), combining the aqueous phases, concentrating the combined aqueous phases under reduced pressure, adding 60mL 2mol/L hydrochloric acid, and at 80 ℃ adding 2mol/L hydrochloric acidStirring for 1 hour, performing suction filtration, washing with 50ml of water, and vacuum drying filter cake to obtain white crystalline powder, namely the target product (3aS,6aR) -lactone (I) (R in the formula I)1Hydrogen, Ar phenyl) (8.3g, 92%).
Example 15
Preparation of (3aS,6aR) -1, 3-dibenzyl-tetrahydro-4H-furo [3,4-d ] imidazole-2, 4(1H) -dione (I)
Placing a newly prepared tetrahydrofuran solution (84mmol,40mL) of potassium borohydride in a dry reaction bottle, dropwise adding a solution of IV (IV prepared in example 1, 20g, 28mmol) dissolved in 60mL of anhydrous tetrahydrofuran at 0 ℃ under stirring, after the dropwise adding, moving to room temperature to react for 10h, after the reaction is finished, adding 100mL of water and 100mL of toluene, stirring at room temperature for 30min, extracting the aqueous phase with toluene three times (50mL × 3) after phase separation, combining the organic phases, washing the combined organic phases with water twice (50mL × 2), combining the aqueous phases, concentrating the combined aqueous phase under reduced pressure, adding 60mL of 2mol/L hydrochloric acid, stirring at 80 ℃ for 1h, performing suction filtration, washing with 50mL of water, and performing vacuum drying on a filter cake to obtain white crystalline powder, namely the target product (3aS,6aR) -lactone (I) (R in formula I)1Hydrogen, Ar phenyl) (8.55g, 95%).
Example 16
Preparation of (3aS,6aR) -1, 3-dibenzyl-tetrahydro-4H-furo [3,4-d ] imidazole-2, 4(1H) -dione (I)
Placing a newly prepared tetrahydrofuran solution (84mmol,40mL) of calcium borohydride in a dry reaction bottle, dropwise adding a solution of IV (IV prepared in example 1, 20g, 28mmol) dissolved in 60mL of anhydrous tetrahydrofuran at 0 ℃ under stirring, after the dropwise adding, moving to room temperature to react for 15h, after the reaction is finished, adding 100mL of water and 100mL of toluene, stirring at room temperature for 30min, extracting the aqueous phase with toluene three times (50mL × 3) after phase separation, combining the organic phases, washing the combined organic phases with water twice (50mL × 2), combining the aqueous phases, concentrating the combined aqueous phase under reduced pressure, adding 60mL of 2mol/L hydrochloric acid, stirring at 80 ℃ for 1h, performing suction filtration, washing with 50mL of water, and performing vacuum drying on a filter cake to obtain white crystalline powder, namely the target product (3aS,6aR) -lactone (I) (R in formula I)1Hydrogen, Ar phenyl) (8.55g, 95%).
Example 17
Preparation of (3aS,6aR) -1, 3-dibenzyl-tetrahydro-4H-furo [3,4-d ] imidazole-2, 4(1H) -dione (I)
This example is the same as example 13, except that the hydrochloric acid in example 13 was replaced with sulfuric acid of the same concentration. The reaction was complete and worked up to give the desired product (I) (8.50g, 94.7%).
Example 18
Preparation of (3aS,6aR) -1, 3-dibenzyl-tetrahydro-4H-furo [3,4-d ] imidazole-2, 4(1H) -dione (I)
This example is the same as example 13, except that the hydrochloric acid in example 13 was replaced with phosphoric acid of the same concentration. The reaction was complete and worked up to give the desired product (I) (8.48g, 94%).
Example 19
Preparation of (3aS,6aR) -1, 3-dibenzyl-tetrahydro-4H-furo [3,4-d ] imidazole-2, 4(1H) -dione (I)
This example is the same as example 13, except that the hydrochloric acid in example 13 was replaced with nitric acid of the same concentration. The reaction was complete and worked up to give the desired product (I) (8.50g, 94.2%).
Example 20
Preparation of (3aS,6aR) -1, 3-bis (1-p-tolylethyl) -tetrahydro-4H-furo [3,4-d ] imidazole-2, 4(1H) -dione (I)
The compound (IV) in this example was prepared as in example 1, except that R in the cyclic anhydride (II) as the substrate used in this example was1Is methyl, Ar is p-tolyl, the resulting compound (IV) is a white powder, R in the compound (IV)1Is methyl, Ar is p-tolyl, R2Is hydrogen, R3Is hydrogen and M is a lithium cation. The yield of the compound (IV) in this step was 95%, and the de value was 100%. Compound (IV) of this example Compound (I) was prepared as in example 13, except that this example used Compound (IV) prepared in this example to obtain the desired product (I) as a white crystalline powder in a yield of 96%.
Example 21
Preparation of (3aS,6aR) -1, 3-bis (1-p-3, 4, 5-trimethylphenyl-p-methoxybenzyl) -tetrahydro-4H-furo [3,4-d ] imidazole-2, 4(1H) -dione (I)
The preparation of the compound (IV) of this example was the same as in example 1 except that R in the cyclic anhydride (II) as the substrate used in this example was1P-methoxyphenyl, Ar is p-3, 4, 5-trimethylphenyl, and the obtained compound (IV) is white powder, R in the compound (IV)1Is p-methoxyphenyl, Ar is p-3, 4, 5-trimethylphenyl, R2Is hydrogen, R3Is hydrogen and M is a lithium cation. The yield of the compound (IV) in this step was 94%, and the de value was 100%. Compound (IV) of this example Compound (I) was prepared as in example 13, except that this example used Compound (IV) prepared in this example to obtain the desired product (I) as a white crystalline powder in a yield of 95%.
It should be noted that, although the above embodiments have been described herein, the invention is not limited thereto. Therefore, based on the innovative concepts of the present invention, the technical solutions of the present invention can be directly or indirectly applied to other related technical fields by making changes and modifications to the embodiments described herein, or by using equivalent structures or equivalent processes performed in the content of the present specification and the attached drawings, which are included in the scope of the present invention.
Claims (9)
1. A stereoselective synthesis method of (3aS,6aR) -lactone is characterized in that a synthesis route is aS follows:
in the formula, R1Is hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, phenyl, p-tolyl, p-methoxyphenyl, 3, 4-dimethylphenyl, 3, 4-dimethoxyphenyl, 3,4, 5-trimethylphenyl, 3,4, 5-trimethoxyphenyl or p-chlorophenyl, Ar is phenyl, p-tolyl, p-methoxyphenyl, 3, 4-dimethylphenyl, 3, 4-dimethoxyphenyl, 3,4, 5-trimethylphenyl, 3,4, 5-trimethoxyphenyl, p-chlorophenylChlorophenyl, thienyl, furyl or naphthyl;
R2is hydrogen, fluorine, chlorine, bromine, iodine, C1-C6Alkyl radical, C3-C6Cycloalkyl or C1-C6An alkoxy group; r3Is hydrogen, fluorine, chlorine, bromine, iodine, C1-C6Alkyl radical, C3-C6Cycloalkyl or C1-C6An alkoxy group;
m is an alkali metal or alkaline earth metal cation;
the synthesis comprises the following specific steps:
step (1): the cyclic anhydride (II) and chiral auxiliary propylene glycol (III) are subjected to a de-symmetrization reaction in a first organic solvent in the presence of an organic base, and then subjected to a double decomposition reaction with an aqueous solution of metal hydroxide to be converted into a dicarboxylic acid monoester salt (IV);
step (2): carrying out reduction reaction on the dicarboxylic acid monoester salt (IV) prepared in the step (1) and borohydride in a second organic solvent, and then carrying out ring closure reaction under the catalysis of inorganic mineral acid to obtain a target product (3aS,6aR) -lactone (I);
the structural formula of the cyclic anhydride (II) is as follows:
in the formula, R1And Ar are as above;
the propylene glycol (III) is (S) -1,2 propylene glycol, and the structural formula is as follows:
in the formula, R2And R3The same as above;
the dicarboxylic acid monoester salt (IV) comprises two diastereomers (IV a) and (IV b):
in the formula, R1、Ar、R2And R3As above, M is an alkali metal or alkaline earth metal cation;
the structural formula of the target product (3aS,6aR) -lactone (I) is aS follows:
in the formula, R1And Ar is as above.
2. The process for the stereoselective synthesis of (3aS,6aR) -lactone according to claim 1, wherein in step (1), the organic base is an organic tertiary amine selected from one of triethylamine, tripropylamine, triisobutylamine, tri-n-butylamine, tripentylamine, trihexylamine, triheptylamine, trioctylamine, 1, 4-diazabicyclo [2.2.2] octane (DABCO), 4-dimethylaminopyridine, 1, 8-diazabicycloundecen-7-ene (DBU), or a mixture of more thereof;
the first organic solvent is selected from one of benzene, toluene, xylene, anisole, fluorobenzene, chlorobenzene, bromobenzene, dichloromethane, trichloromethane, 1, 2-dichloroethane, tetrahydrofuran, 1, 4-dioxane, ethylene glycol dimethyl ether, diethyl ether, N-hexane, cyclohexane, acetonitrile, acetone, N-dimethylformamide, N-dimethylacetamide, dimethyl sulfoxide, N-methylpyrrolidone, sulfolane, 1, 3-dimethyl-2-imidazolidinone, hexamethylphosphoric triamide, N-alkylpyridinium salt, 1, 3-dialkylimidazolium salt, or a mixed solvent of a plurality of the above.
3. The method for stereoselective synthesis of (3aS,6aR) -lactone according to claim 1, wherein in the step (1), the molar ratio of the cyclic anhydride (II), the chiral auxiliary, propylene glycol (III) and the organic base is controlled within the range of 1 (0.8-1.5) to (0.1-2.0).
4. The method for stereoselective synthesis of (3aS,6aR) -lactone according to claim 1, wherein the temperature of the de-symmetrization reaction in step (1) is controlled within the range of-20 to 80 ℃ and the reaction time is controlled within the range of 2 to 48 hours.
5. The process for the stereoselective synthesis of (3aS,6aR) -lactone according to claim 1, wherein the metal hydroxide in step (1) is an alkali metal hydroxide or an alkaline earth metal hydroxide, selected from one of lithium hydroxide, sodium hydroxide, potassium hydroxide, magnesium hydroxide, calcium hydroxide, barium hydroxide, or a mixture of more thereof.
6. The method for stereoselective synthesis of (3aS,6aR) -lactone according to claim 1, wherein the amount of the metal hydroxide charged in the metathesis reaction in step (1) is controlled so that the molar ratio of the metal hydroxide to the cyclic anhydride (II) is (1-1.8): 1.
7. The process for the stereoselective synthesis of (3aS,6aR) -lactone according to claim 1, characterized in that in step (2):
the second organic solvent is one of tetrahydrofuran, 2-methyltetrahydrofuran, 1, 4-dioxane, methanol, ethanol, isopropanol and glycol, or a mixed solvent of a plurality of the solvents;
the borohydride is selected from any one of lithium borohydride, sodium borohydride, potassium borohydride and calcium borohydride;
the inorganic mineral acid is selected from any one of hydrochloric acid, sulfuric acid, nitric acid and phosphoric acid.
8. The method for stereoselective synthesis of (3aS,6aR) -lactone according to claim 1, wherein the molar ratio of said dicarboxylic acid monoester salt (IV) to borohydride in step (2) is controlled to be in the range of 1 (1-4).
9. The process for the stereoselective synthesis of (3aS,6aR) -lactone according to claim 1, wherein in step (2), the temperature of the reduction reaction is controlled in the range of 0 to 100 ℃; the temperature of the ring closing reaction is controlled within the range of 20-150 ℃.
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| CN115466217B (en) * | 2022-09-26 | 2024-01-30 | 安徽泰格维生素实业有限公司 | Method for recycling cyclic acid |
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