CN104478845A - Preparation method of fluorine lactone intermediate - Google Patents

Preparation method of fluorine lactone intermediate Download PDF

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Publication number
CN104478845A
CN104478845A CN201410719145.7A CN201410719145A CN104478845A CN 104478845 A CN104478845 A CN 104478845A CN 201410719145 A CN201410719145 A CN 201410719145A CN 104478845 A CN104478845 A CN 104478845A
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compound
preparation
formula
described formula
methyl acrylate
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CN104478845B (en
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杜小华
何大伟
车大庆
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Zhejiang Raybow Pharmaceutical Co ltd
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Zhejiang Jiuzhou Pharmaceutical Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/10—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings
    • C07D317/14—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D317/30—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

The invention relates to the technical field of organic chemistry, and particularly a preparation method of a fluorine lactone intermediate. The method comprises the following step: preparing a compound disclosed as Formula I from a compound disclosed as Formula II in the presence of sodium borohydride and Lewis acid.

Description

A kind of preparation method of fluorine lactone intermediate
Technical field
The present invention relates to technical field of organic chemistry, particularly relate to a kind of preparing technical field of fluorine lactone intermediate.
Background technology
Lactone compound is extensively present in occurring in nature, they are not only the main functional group of some natural products, as alkaloid, macrocyclic antibiotic, lignanoid's lactones, hormone lactone, plant-growth regulator, spices, still there is bioactive material and Metabolic Intermediate; Little by little, it should be noted that in organic molecule that optionally introducing fluorine atom can make its physiologically active that beyond thought change occurs, fluorine atom or fluoro-containing group are incorporated in lactone compound molecule, the electronic center of compound can be made to offset, its biological activity is changed, so this field seems increasingly active.Therefore the synthesis of lactone compound is the research field that people are concerned about very much always, is not only used for synthesis of natural product, is also used for synthesizing some fine chemical products and medicine intermediate, as fluorine lactone.
The compound with following formula I structure is the important intermediate of synthesis fluorine lactone:
Under normal circumstances this formula I be with for raw material with generation Wittig reaction prepares, such as document Journal of the American Chemical Society, and 125 (29), 8734-8735,2003 just employ the method.
Witting reagent (Witting) loses the preparation of a part hydrogen halide with Si Ji phosphonium salt usually under highly basic effect, and highly basic selects phenyl lithium or n-Butyl Lithium usually.Witting reagent character is active, all unstable to water and air; And with the generation of triphenylphosphine oxide while generating alkene by Witting reagent and corresponding aldehyde reaction, therefore need column chromatography purification, but triphenylphosphine oxide is difficult to removing completely easily to be remained in the product, thus affect the quality standard of product.
This is necessary to the preparation method developing new formula I, thus solves Problems existing in existing route, to meet the demand that industrialization generates.
Summary of the invention
The invention provides a kind of preparation method of formula I,
The compound be specially by having formula II structure prepares under sodium borohydride and Lewis acid exist,
Preferred described Lewis acid is CuCl 2, BF 3, FeCl 3, AlCl 3, ZnCl 2, SnCl 4, CeCl 3or Al 2o 3;
Preferred described Lewis acid is CuCl 2, CeCl 3or Al 2o 3; Wherein said CuCl 2can be its crystalline hydrate, such as CuCl 22H 2o.
Preferred described method is: described formula II compound, under sodium borohydride and Louis acid exist, is obtained by reacting described formula I under in organic solvent in 20 DEG C to reflux temperature.
Preferred described method is: described formula II compound is being CuCl 2, CeCl 3or Al 2o 3under existence, in organic solvent in 30-35 DEG C of reaction, reaction solution to weakly alkaline, then uses hexane extraction through aqueous ammonium chloride solution process, and concentrated hexane extract obtains described formula I.
Wherein said organic solvent is preferably alcoholic solvent, and described alcoholic solvent is preferably methyl alcohol, ethanol or Virahol.
Described formula II compound is preferably 1:(1.5 ~ 3 with the mole dosage ratio of sodium borohydride);
Described formula II compound and lewis acidic mole dosage are than being preferably 1:(0.06 ~ 2).
Further, described formula II compound is prepared in the presence of a catalyst by following formula III compound and methyl acrylate,
Wherein said catalyzer is tertiary amine or tertiary phosphine
Wherein said tertiary amine is selected from tri-n-butylamine, DBU (1,8-diazabicylo 11 carbon-7-alkene); Described tertiary phosphine is selected from trimethyl-phosphine, tri-butyl phosphine.
Further, comprise the step adding cocatalyst in the reaction, described cocatalyst is 1,1'-union-2-naphthol.
Preferably, described formula II compound is by described formula III compound and methyl acrylate under catalyzer and 1,1'-union-2-naphthol exist, and in the reaction of 30 DEG C-reflux temperature, reaction solution organic solvent extraction, obtains formula II compound after organic layer is concentrated.
Wherein said organic solvent is preferably methylene dichloride.
Described formula III compound is 1:(1.1 ~ 2 with the mole dosage ratio of methyl acrylate);
Described formula III compound is 1:(0.2 ~ 0.6 with the mole dosage ratio of catalyzer);
Described formula III compound is 1:(0.02 ~ 0.1 with the mole dosage ratio of cocatalyst).
Embodiment
Content for a better understanding of the present invention, is described further below in conjunction with specific embodiment, but concrete embodiment is not the restriction done content of the present invention.
The preparation of embodiment 1:3-[(4R)-2,2-dimethyl-DOX-4-base]-2-methylene radical-3-hydroxyl-2-methyl acrylate
(R)-(+)-2 is dropped in the reaction flask of 500ml, 2-dimethyl-1, 3-dioxolane-4-formaldehyde (65g, 0.5mol), tri-n-butylamine (40g, 0.22mol) with methyl acrylate (65g, 0.76mol), be heated to 30-40 DEG C, be incubated 16 hours, 300ml methylene dichloride and 100ml water is added in reaction flask, stir, layering, organic layer 2*100ml water washing 2 times, 1 time is washed again with the acetic acid of 100ml 10%, finally wash 1 time with 50ml saturated sodium bicarbonate solution, organic layer concentrating under reduced pressure removes methylene dichloride and low boilers, obtain 3-[(4R)-2, 2-dimethyl-1, 3-dioxolane-4-base]-2-methylene radical-3-hydroxyl-2-methyl acrylate 84g, yield 68.3%, GC purity 93.5%.
The preparation of example 2:3-[(4R)-2,2-dimethyl-DOX-4-base]-2-methylene radical-3-hydroxyl-2-methyl acrylate
(R)-(+)-2 is dropped in the reaction flask of 500ml, 2-dimethyl-1,3-dioxolane-4-formaldehyde (65g, 0.5mol), DBU (30g, 0.2mol), methyl acrylate (65g, 0.76mol) and 200ml methylene dichloride, be heated to backflow, be incubated 8 hours.Cooling, adds 100ml methylene dichloride and 100ml water in reaction flask, stirs, layering, organic layer 2*100ml water washing 2 times, then wash 1 time with the acetic acid of 100ml 10%, finally wash 1 time with 50ml saturated sodium bicarbonate solution, organic layer concentrating under reduced pressure removes methylene dichloride and low boilers, obtain 3-[(4R)-2,2-dimethyl-DOX-4-base]-2-methylene radical-3-hydroxyl-2-methyl acrylate 91.67g, yield 75.8%, GC purity 95.1%.
The preparation of example 3:3-[(4R)-2,2-dimethyl-DOX-4-base]-2-methylene radical-3-hydroxyl-2-methyl acrylate
(R)-(+)-2 is dropped in the reaction flask of 500ml, 2-dimethyl-DOX-4-formaldehyde (32g, 0.25mol), 8 grams of trimethyl-phosphine (8g, 0.1mol), 1,1'-union-2-naphthol (5g, 0.017mol), methyl acrylate (30g, 0.35mol) and 300mlTHF, be heated to 50-60 DEG C, be incubated 16 hours.Concentrating under reduced pressure removes THF, 250ml methylene dichloride is added in raffinate, use 100ml water washing successively, the sodium carbonate solution of 100ml 20%, 50ml water washing, organic layer concentrating under reduced pressure removes methylene dichloride and low boilers, obtain 3-[(4R)-2,2-dimethyl-DOX-4-base]-2-methylene radical-3-hydroxyl-2-methyl acrylate 49.2g, yield 80.1%, GC purity 93.6%.
The preparation of example 4:3-[(4R)-2,2-dimethyl-DOX-4-base]-2-methylene radical-3-hydroxyl-2-methyl acrylate
(R)-(+)-2 is dropped in the reaction flask of 500ml, 2-dimethyl-DOX-4-formaldehyde (32g, 0.25mol), tri-butyl phosphine (12g, 0.06mol), 1,1'-union-2-naphthol (5g, 0.017mol), methyl acrylate (30g, 0.35mol) and 300mlTHF, be heated to 50-60 degree, be incubated 16 hours.Concentrating under reduced pressure removes THF, 250ml methylene dichloride is added in raffinate, use 100ml water washing successively, the sodium carbonate solution of 100ml 20%, 50ml water washing, organic layer concentrating under reduced pressure removes methylene dichloride and low boilers, obtain 3-[(4R)-2,2-dimethyl-DOX-4-base]-2-methylene radical-3-hydroxyl-2-methyl acrylate 53.57g, yield 87.3%, GC purity 93.7%.
Example 5:(2E) preparation of-3-[(4S)-2,2-dimethyl-DOX-4-base]-2-methyl-2-methyl acrylate
3-[(4R)-2 is added in 500ml reaction flask; 2-dimethyl-1; 3-dioxolane-4-base]-2-methylene radical-3-hydroxyl-2-methyl acrylate (23g; 0.1mol), 300ml methyl alcohol, adds sodium borohydride (8g under nitrogen protection; 0.21mol); copper chloride dihydrate (20g, 0.13mol), is warming up to 30-35 degree vigorous stirring and is incubated 2 hours.Add saturated ammonium chloride solution 30ml, maintenance system is weakly alkaline, and the most of methyl alcohol of decompression removing, adds hexane extraction product in raffinate, hexane layer 50ml water washing 1 time, concentrated removing hexane, obtains (2E)-3-[(4S)-2,2-dimethyl-1,3-dioxolane-4-base]-2-methyl-2-methyl acrylate crude product, crude product obtains sterling 18.9 grams through molecular distillation purifying, yield 88.4%, GC purity E+Z=95.8% (E/Z=94.2/1.6).
Example 6:(2E) preparation of-3-[(4S)-2,2-dimethyl-DOX-4-base]-2-methyl-2-methyl acrylate
3-[(4R)-2 is added in 500ml reaction flask; 2-dimethyl-1; 3-dioxolane-4-base]-2-methylene radical-3-hydroxyl-2-methyl acrylate (23g; 0.1mol), 300ml methyl alcohol, adds sodium borohydride (8g under nitrogen protection; 0.21mol); cerous compounds (24g, 0.06mol), is warming up to 30-35 degree vigorous stirring and is incubated 2 hours.Add saturated ammonium chloride solution 30ml, maintenance system is weakly alkaline, the most of methyl alcohol of decompression removing, hexane extraction product is added in raffinate, hexane layer 50ml water washing 1 time, concentrated removing hexane, obtain (2E)-3-[(4S)-2,2-dimethyl-1,3-dioxolane-4-base]-2-methyl-2-methyl acrylate crude product, crude product obtains sterling 16.63 grams through molecular distillation purifying, yield 77.7%, GC purity E+Z=92.6% (E:Z=92.6:0).
Example 7:(2E) preparation of-3-[(4S)-2,2-dimethyl-DOX-4-base]-2-methyl-2-methyl acrylate
300ml ethanol is added in 500ml reaction flask; sodium borohydride (8g is added under nitrogen protection; 0.21mol); activated basic alumina (15g, 0.15mol), then adds 3-[(4R)-2; 2-dimethyl-1; 3-dioxolane-4-base]-2-methylene radical-3-hydroxyl-2-methyl acrylate (23g, 0.1mol), be warming up to backflow vigorous stirring and be incubated 4 hours.Add saturated ammonium chloride solution 30ml, filter, filtrate decompression removes most of ethanol, adds hexane extraction product in raffinate, hexane layer 50ml water washing 1 time, concentrated removing hexane, obtains (2E)-3-[(4S)-2,2-dimethyl-1,3-dioxolane-4-base]-2-methyl-2-methyl acrylate crude product, crude product obtains sterling 14.8 grams through molecular distillation purifying, yield 69.3%, GC purity E+Z=97.6% (E:Z=96.5:1.1).
Embodiment 8-12 operates with method according to the method for embodiment 5, uses different lewis acid catalyst (described formula II compound with lewis acidic mole dosage than be 1:(0.06 ~ 2) instead) test-results that obtains:
Embodiment Lewis acid catalyst Yield GC purity
8 BF 3 34.5％ E+Z＝91.6％(E：Z＝89.4：2.2)
9 FeCl 3 39.4％ E+Z＝89.9％(E：Z＝87.8：2.1)
10 AlCl 3 58.6％ E+Z＝92.6％(E：Z＝90.6：2.0)
11 ZnCl 2 50.4％ E+Z＝87.8％(E：Z＝86.6：1.1)
12 SnCl 4 42.3％ E+Z＝92.5％(E：Z＝92.5：0)
Although combined embodiment to invention has been sufficient description, should be noted that its variations and modifications are apparent to those skilled in the art.Such change and amendment it will be appreciated that as being included in the scope of the present invention that defined by claims.

Claims (10)

1. the preparation method of formula (I) compound, is prepared under sodium borohydride and Lewis acid exist by following formula (II) compound,
2. preparation method according to claim 1, described Lewis acid is CuCl 2, BF 3, FeCl 3, AlCl 3, ZnCl 2, SnCl 4, CeCl 3or Al 2o 3.
3. preparation method according to claim 1, described formula (II) compound is under sodium borohydride and Louis acid exist, be obtained by reacting described formula (I) compound under in organic solvent in 20 DEG C to reflux temperature, wherein said Lewis acid is CuCl 2, BF 3, FeCl 3, AlCl 3, ZnCl 2, SnCl 4, CeCl 3or Al 2o 3.
4. preparation method according to claim 1, described formula (II) compound is being CuCl 2, CeCl 3or Al 2o 3under existence, in organic solvent in 30-35 DEG C of reaction, reaction solution to weakly alkaline, then uses hexane extraction through aqueous ammonium chloride solution process, and concentrated hexane extract obtains described formula (I) compound.
5. the preparation method according to claim 3 or 4, described organic solvent is alcoholic solvent, and described alcoholic solvent is selected from methyl alcohol, ethanol and Virahol.
6. preparation method according to claim 1, comprises step further, and described formula (II) compound is prepared in the presence of a catalyst by following formula (III) compound and methyl acrylate,
Wherein said catalyzer is selected from tertiary amine or tertiary phosphine.
7. preparation method according to claim 6, comprises the step adding cocatalyst further, and described cocatalyst is 1,1'-union-2-naphthol.
8. preparation method according to claim 6, described formula (II) compound by described formula (III) compound and methyl acrylate at catalyzer and 1, under 1'-union-2-naphthol exists, in 30-40 DEG C of reaction, reaction solution organic solvent extraction, obtains formula (II) compound after organic layer is concentrated.
9. preparation method according to claim 8, described formula (III) compound is 1:(0.2 ~ 0.6 with the mole dosage ratio of described catalyzer).
10. preparation method according to claim 8, the mole dosage of described formula (III) compound and 1,1'-union-2-naphthol is than being 1:(0.02 ~ 0.1).
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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102408405A (en) * 2011-09-09 2012-04-11 陶克美 Preparation method of medicament intermediates capable of resisting hepatitis C virus
CN103159730A (en) * 2011-12-19 2013-06-19 江苏威凯尔医药科技有限公司 Hepatitis-C-resisting drug intermediate preparation method

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102408405A (en) * 2011-09-09 2012-04-11 陶克美 Preparation method of medicament intermediates capable of resisting hepatitis C virus
CN103159730A (en) * 2011-12-19 2013-06-19 江苏威凯尔医药科技有限公司 Hepatitis-C-resisting drug intermediate preparation method

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Patentee before: ZHEJIANG JIUZHOU PHARMACEUTICAL Co.,Ltd.