CN101468936A - Method for synthesizing alcoholic hydroxyl fluorine derivatives - Google Patents
Method for synthesizing alcoholic hydroxyl fluorine derivatives Download PDFInfo
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- CN101468936A CN101468936A CNA2008100716092A CN200810071609A CN101468936A CN 101468936 A CN101468936 A CN 101468936A CN A2008100716092 A CNA2008100716092 A CN A2008100716092A CN 200810071609 A CN200810071609 A CN 200810071609A CN 101468936 A CN101468936 A CN 101468936A
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Abstract
The invention discloses a method for synthesizing alcoholic hydroxyl group fluoro derivatives, which belongs to the technical field of chemosynthesis. In the presence of organic amine and organic solvent, PBSF and TBAT are jointly used as fluorination reagents and subjected to fluorination with hydroxyl derivatives, so as to obtain the alcoholic hydroxyl group fluoro derivatives. The synthesis method has the advantages of greatly reducing and eliminating byproducts, reducing the amount of the TBAT to an equivalent below 1.2, completely inverting the configuration of the fluorination of chiral alcoholic hydroxyl under mild conditions and reducing optical isomer impurities.
Description
Technical field
The present invention relates to a kind of synthetic method, specifically be meant with PBSF and TBAT and unite use, alcoholic extract hydroxyl group is carried out the fluoric new synthetic method as fluorination reagent.
Background technology
Fluorine element exists with carbon-fluorine bond form usually in medicine, potent in contemporary many treatments field, the medicine of low toxicity all contains fluorine element, as Norxin, Ciprofloxacin, Sitafloxacin, Clofarabine, fluocinolone acetonide etc., this is because carbon-fluorine bond has unique biological living features (Welch, J.T.Tetrehedron 1987,43, and 3123).The direct method of carbon-fluorine bond form one is that alcoholic extract hydroxyl group is replaced (Yoneda, N.Tetrahedron 1991,47,5329) by fluorine.The fluoro reagent of early development has SF
4(Wang, C.L.J.Org.React.1985,34,319), Olah reagent (Olah, G.A.Nojima, M.; Kerekes, I.J.Am.Chem.Soc.1974,96,925) and analogue [a) .Olah, G.A.et al.Synthesis 1993,693; B) .Yoneda, N.et al.Chem.Lett.1983,1135; C) .Wiechert, D.et al.J.Am.Chem.Soc.1997,119,12665], ether and hydrofluoric mixture (Olah, G.A.et al.J.Am.Chem.Soc.2002,124,7728) fluoro hydroxylamine reagent [a) .Takaoka, A.et al.Bull.Chem.Soc.Jpn.1979,52,3377; B) .Dmowski, W et al.J.Fluorine Chem.1983,23,219; C) .Petrov, V.A.et al.J.Fluorine Chem.2001,109,25], DFI (Hayashi, H et al.Chem.Commun.2002,1618), IF
5/ Et
3N3HF (Yoneda, N.; Fukuhara, T.Chem.Lett.2001,222), DAST (Middleton, W.J.J.Org.Chem.1975,40,574) and analogue BAST (Lal, G.S.etal.J.Org.Chem.1999,64,7048). these reagent all exist these problems or these problems of part: severe toxicity, danger, instability, be difficult to operation, need harsh reaction conditions, deep-etching, reaction yield is low, is difficult for preparation, costs an arm and a leg etc.These reagent all react under acidic conditions in addition, and its process has fatal HF to produce.
In recent years perfluor normal-butyl sulfonic acid fluoride (PBSF) by electrolysis process in the ground scale operation of industrial one-tenth ton.PBSF is a kind of fluorination reagent [(a) .Bennua-Skalmowski.B.et al.Tetrahedron Lett.1995,36,2611 of exploitation in recent years in conjunction with 1.8-diazabicylo (5.4.0) 11 rare-7 (DBU); B) .Takamatsu S.et al.Nucleosides, Nucleotides﹠amp; Nucleic Acids.2002,21,849; C) .Richard A.D.and Charles M.M.Synth.Commun.2004,34,4369], it can be with alcoholic hydroxyl fluorine under mild conditions.But reaction yield is on the low side (less than 70%), eliminates product many (can reach 30～40%) and causes separation difficulty thus; For the chiral alcohol hydroxyl, the optical isomer impurity that exists a small amount of configuration not overturn in its fluoro product.
The positive TBuA of triphenyl bifluoride silicon (TBAT, Ph
3SiF
2 - +NBu
4) can make (Christopher J.H.et al.J.Org.Chem.2000,65,3542) by triphenyl silanol and tetra-n-butyl Neutral ammonium fluoride easily, it shows neutral, and non-hygroscopic property is very stable, can exist by anhydrous form.TBAT needs alcoholic extract hydroxyl group is transformed into sulphonate (as: methanesulfonates, trifluoro sulphonate, p-toluenesulfonic esters) earlier as fluoro reagent, and refluxes in acetonitrile and finish reaction; Its shortcoming also has: needing very excessive TBAT, need 4 equivalent TBAT approximately for primary alcohol, need 6 equivalent TBAT approximately for secondary alcohol, and the elimination product of a great deal of is arranged, mainly is to eliminate product for tertiary alcohol, and a spot of fluoro product is only arranged; The isomer impurities (Picher, A.S.et al J.Am.Chem.Soc.1995,117,5166) that has the part configuration not overturn for the fluoro product of chiral alcohol.These shortcomings have seriously limited its application as fluoro reagent.
Summary of the invention
The objective of the invention is to problem at above-mentioned prior art existence, a kind of synthetic method of alcoholic hydroxyl fluorine derivatives is provided, under mild conditions, utilization is easy to get inexpensive fluorination reagent with 1, the hydroxyl of 2 grades of Fatty Alcohol(C12-C14 and C12-C18) carries out fluoro-reaction, and reduce and eliminate by product, and reduce the unturned optical isomer of configuration.
The technical scheme that the present invention takes for achieving the above object is, a kind of synthetic method of alcoholic hydroxyl fluorine derivatives, it is characterized in that: under organic amine and organic solvent existence condition, unite and use PBSF and TBAT to carry out fluoro-reaction, obtain the alcoholic hydroxyl fluorine derivatives of representing suc as formula 2 as the hydroxy derivatives of fluorination reagent and formula 1 expression.
(formula 1) (formula 2)
In formula 1 and the formula 2: R
1, R
2Can be H independently of one another, alkyl, aromatic base or the alkyl that is substituted, aromatic base, the ether of aromatic base, tertiary amine, ester group, the two keys in β position are to unsettled trityl nitrogen of acid or oxygen base, α position carbonyl.
In the synthetic method of the present invention:
The hydroxy derivatives that adopts is preferably 1,2 grade of Fatty Alcohol(C12-C14 and C12-C18), wherein: can contain ester group or aryl ethers in 1 grade of pure molecule, to the unsettled trityl of acid (TrN, TrO), the β position two strong; Along with sterically hindered increase, speed of response slows down, and causes that yield descends; It is better to contain tertiary amine fluoro-reaction effect in the chiral alcohol molecule; For the Alpha-hydroxy of carbonyl, the fluoro effect is fine.
The PBSF and the organic amine that adopt all are excessive, if the PBSF consumption very little, then raw material is failed by completely consumed, and wherein the consumption of PBSF is when 1.5～2.5 times of equivalents of raw material, and reaction can transform fully, and be best at 1.8～2.2 times of equivalents.Because of the TBAT acid labile, usually the consumption of organic amine is that 1.1 times of PBSF are more than the equivalent.
And the consumption of TBAT is in that to be lower than 1.2 times of equivalent internal efficiencies best.This be because, consumption very little, it is many to eliminate product, the optical purity of product descends, and more excellent is controlled at 0.8～1.2 times of equivalent; As embodiment 1-1, alcohol (2S, 4R)-1 in toluene, make alkali, do not add TBAT, fluoro product (2S with triethylamine, only be 2.4:1 4S)-2 with the ratio of eliminating product [(2S)-3+ (2S)-4], and when adding TBAT and reaching 0.8 equivalent,, make alkali with diisopropylethylamine as embodiment 1-9, (2S 4S)-2 just reaches 14:1 with the ratio of eliminating product [(2S)-3+ (2S)-4] to the fluoro product; Use toluene instead tetrahydrofuran (THF) and make solvent, reach 21:1 as embodiment 1-9 fluoro product and the ratio of eliminating product.Along with the consumption of TBAT rises to 1.2 equivalents, the fluoro product reaches 18:1 with the ratio of eliminating product in toluene, the fluoro product still is 21:1 with the ratio of eliminating product in tetrahydrofuran (THF), and this presentation of results increases TBAT again, and it is not remarkable that it reduces the effect increase of eliminating product.To chiral alcohol, as (2S, 4R)-1, the optical purity of its fluoro product also improves along with the adding of TBAT.
Equivalent of the present invention also can be exchanged into the mol ratio of raw material (hydroxy derivatives).
Temperature of reaction of the present invention raises, and speed of response increases, but eliminates the ratio rising of product, and the optical purity of product descends; Temperature descends, and speed of response descends, and the ratio of eliminating product slightly descends, and the optical purity of product slightly rises.Generally speaking, can obtain preferable effect under the room temperature condition.
Feeding sequence of the present invention is more excellent to be: pure and mild TBAT, amine, solvent, last PBSF.This be because:
Known Xi Fushi alkali DBU or DBN mix with PBSF earlier, and feeding intake then again, fluoro-reaction can not carry out (Takamatsu, S.et al.Nucleosides, Nucleotides; Nucleic Acids.2002,21,849).Here applied amine also can make PBSF decompose (B.-S.Barbel, et al.Synthesis.2008,1175).So amine prior to PBSF, adds.The TBAT acid labile if contain the acidic substance of trace among solvent or the PBSF, can destroy TBAT.
Organic solvent of the present invention is non-proton and organic solvent that polarity is less, as benzene, and toluene, dimethylbenzene, aromatic hydrocarbons such as chlorobenzene; Tetrahydrofuran (THF), 2-methyltetrahydrofuran, ether, isopropyl ether, ethers such as tirethylene glycol dme; Methylene dichloride, 1, halogenated hydrocarbons such as 2-ethylene dichloride.Producing the ratio of eliminating by product in homogeneous solvent not is: tetrahydrofuran (THF)＜toluene＜methylene dichloride, but fluoro-reaction is slower in the tetrahydrofuran (THF) speed of response, and transform not exclusively (table 1).
Organic amine of the present invention is preferably the aliphatic hydrocarbon tertiary amine, as: triethylamine (TEA), triethylene diamine (DABCO), diisopropyl methylamine, diisopropylethylamine (iPr
2NEt), N-methyl piperidine, N, N-dimethylcyclohexylamine; Xi Fushi alkali also is suitable in addition, as 1.8-diazabicylo (5.4.0) 11 hydrocarbon-7-alkene (DBU), and 1.5-diazabicylo (4.3.0) ninth of the ten Heavenly Stems-5-alkene (DBN) etc.The DBU that using basic is stronger, speed of response is very fast, but causes more elimination product; Use sterically hindered big amine such as diisopropylethylamine and help reducing the elimination product; Product is then eliminated in the consumption increase of amine increases (table 1).
Beneficial effect of the present invention is: adopt synthetic method of the present invention, reduce significantly and eliminate by product, reduced the following equivalent of consumption to 1.2 of TBAT, under mild conditions, for the fluoro of chiral alcohol hydroxyl, its configuration overturns fully, has reduced optical isomer impurity.
The invention will be further described below in conjunction with embodiment, but this explanation is not construed as limiting the invention.
Embodiment
According to synthetic method of the present invention, with (2S 4R)-1 is a reaction raw materials, and the situation that obtains alcoholic hydroxyl fluorine derivatives under difference batching and reaction conditions is as shown in table 1:
Table 1: so that (2S 4R)-1 is the fluoro result of reaction raw materials under various proportionings and reaction conditions
Its reaction equation is as follows:
In the table 1: embodiment 1-4
At room temperature drop into successively (2S, and 4R)-1 (5.00g, 16.6mmol), TBAT (5.39g, 10.0mmol), triethylamine (5.81ml, 4.22g, 41.8mmol) and toluene 80ml, add after the stirred for several minute PBSF (11.0g, 36.5mmol), stirring reaction 24h, measuring transformation efficiency through HPLC is 99.7%, and the fluoro product is 8.0 with the ratio (F/E) of eliminating product, and the optical purity value of fluoro product is 99.4%; Determine raw material through LC-MS, eliminate product, and the unturned optical isomer of configuration (2S, 4R)-2 and product (2S, 4S)-2 position on HPLC figure; And with elimination product that is separated to [(2S)-3+ (2S)-4] and fluoro product [(2S, 4S)-2] on HPLC, comparing. reaction mixture concentrates through the rotation reduction vaporization, residual oily matter through rapid column chromatography separate the fluoro product (2S, 4S)-2 and eliminate product [(2S)-3+ (2S)-4].
Eliminate product [(2S)-3+ (2S)-4] for two: white crystals, R
f=0.28 (sherwood oil: acetone=80:20); 190～197 ℃ of Mp; Eliminate product RT=11.6min, MS (m/z): 282[M+1 for LC-MS:1 that eliminates product after the column chromatography for separation]
+, 304[M+Na]
+Eliminate product RT=12.7min for 1 in addition; MS (m/z): 282[M+1]
+, 304[M+Na]
+.IR (KBr): 3100,2961,1765,1598,1098,820,802,665cm
-1 1H NMR (CDCl
3): δ=7.79 (d, J=8.2Hz, 2H), 7.71 (d, J=8.2Hz, 2H), 7.36～7.33 (m, 4H), 6.39 (t, J=2.0Hz, 1H), 5.89～5.86 (m, 1H), 5.70～5.65 (m, 1H), 5.16～5.07 (m, 2H), 4.30～4.10 (m, 3H), 3.81 (s, 3H), 2.90～2.66 (m, 2H), 2.45 (s, 3H), 2.44 (s, 3H).
The fluoro product (2S, 4S)-2: white crystals, R
f=0.44 (sherwood oil: acetone=70:30); Mp:100～103 ℃; IR (KBr) :=3006,2960,1759,1599,1344,673cm
-1.MS (m/z): 302[M+1]
+.
1H NMR (CDCl
3): δ=7.82 (d, J=8.2Hz, 2H), 7.35 (d, J=8.2Hz, 2H), 5.21 (dd, J=50.2/3.2Hz, 1H), 4.67 (d, J=9.4Hz, 1H), 3.73 (s, 3H), 3.58～3.68 (m, 2H), 2.54 (dd, J=15.2/1.4Hz, 1H), 2.46 (s, 3H), 2.22 (dtd, J=32.2/12.3/5.8Hz, 1H).
Annotate:
1.RT: the reaction times
2.Conv: transformation efficiency=[1-surplus stock/(product+optical isomer+elimination product)] * 100%
3.ee: the optical purity of product=[(2S, 4S)-2-(2S, 4R)-2]/[(2S, 4S)-2+ (2S, 4R)-2] * 100%
4.F/E: product/elimination product=[(2S, 4S)-2]/[(2S)-3+ (2S)-4]
5. operation steps and the analytical procedure with embodiment 1 is identical, and reaction conditions and charging capacity are according to the explanation in the table.
6.LC-MS instrument: Agilent 1100series; Analytical column LiChrospher Si 60 (5 μ m, 250 * 4mm, pre-column 4 * 4mm); Flow velocity: 1ml/min; Column temperature: 30 ℃; Sample size: 10 μ l; Moving phase: CH
3OH-H
2O (1:1);
HPLC test condition: instrument Simadzu; Detector: D
2-Lamp; Analytical column LiChrospherSi 60 (5 μ m, 250 * 4mm, pre-column 4 * 4mm); Flow velocity: 1ml/min; Column temperature: 30 ℃; Sample size: 10 μ l; Moving phase: CH
3OH-H
2O (1:1).
In the table 1: embodiment 1-9
At room temperature drop into successively (2S, and 4R)-1 (5.00g, 16.6mmol), TBAT (7.18g, 13.3mmol), diisopropylethylamine 5.77ml (4.19g, 41.5mmol) and toluene 80ml, add after the stirred for several minute PBSF (11.0g, 36.5mmol), stirring reaction 24h, TLC follows the tracks of reaction, rotary evaporation concentrated after reaction was finished, and residue gets white crystals 3.28g through column chromatography, yield 87.0%.
Embodiment 2
At room temperature drop into 9-benzoyloxy-1 nonyl alcohol (3.10g successively, 11.7mmol), TBAT (5.04g, 93.6mmol), diisopropylethylamine (4.82ml, 3.77g, 29.3mmol) and toluene 56ml, add after the stirred for several minute PBSF (7.77g, 25.7mmol), stirring reaction 24h, TLC follows the tracks of reaction.Rotary evaporation concentrated after reaction was finished, and residue gets colorless oil 2.93g through column chromatography, yield 93.9%.R
f=0.38 (sherwood oil: the .IR (NaCl) of acetone=160:1): 3071,2932,2857,1720,1275,1123,714cm
-1MSm/z:267[M+1]
+ 1H NMR (CDCl
3) δ=1.27～1.48 (m, 11H), 1.63～1.81 (m, 4H), 4.32 (t, J=5.3Hz, 2H), 4.44 (dt, J=39.5/5.0Hz, 2H), 7.34～7.58 (m, 3H), 7.65 (d, J=6.0Hz, 1H), 8.05 (d, J=6.0Hz, 1H).
Embodiment 3
At room temperature drop into successively (2S, 4R)-N-[4,4-joins (3-methyl-2-thiophene phenyl)-3-butenyl]-4-hydroxyl Pyrrolizidine-2-methyl-formiate (3.87g, 10.0mmol), TBAT (4.32g, 8.00mmol), diisopropylethylamine (4.16ml, 3.24g, 25.0mmol) and toluene 47ml, add after the stirred for several minute PBSF (6.64g, 22.0mmol), stirring reaction 24h, TLC follows the tracks of reaction.Rotary evaporation concentrated after reaction was finished, and residue gets little yellow oil 3.23g through column chromatography, yield 83.0%.R
f=0.27 (sherwood oil: the .IR (NaCl) 3105,2951,2805,1748,1435,1200,1174 of acetone=20:1), 715cm
-1.MSm/z:394[M+1]
+ 1H NMR (CDCl
3) δ=2.00 (s, 3H), 2.03 (s, 3H), 2.20～2.57 (m, 6H), 2.89～2.98 (m, 1H), 3.20 (s, 1H), 3.37 (dd, J=17.5/10.5Hz, 1H), 3.73 (s, 3H), 5.12 (d, J=45.5Hz, 1H), 6.04 (t, J=5.3Hz, 1H), 6.76 (d, J=3.5Hz, 1H), 6.84 (d, J=3.5Hz, 1H), 7.05 (d, J=3.5Hz, 1H), 7.21 (d, J=3.5Hz, 1H).
Embodiment 4
The Alpha-hydroxy Phenylmethyl benzeneacetate (2.15g, 8.88mmol), TBAT (1.91g, 3.55mmol), (3.09ml, 2.24g 22.2mmol) and toluene 43ml, add PBSF (5.90g after the stirred for several minute to triethylamine, 19.5mmol), stirring reaction 24h, TLC follows the tracks of reaction.Rotary evaporation concentrated after reaction was finished, and residue gets colorless oil 1.97g through column chromatography, yield 90.9%.R
f=0.14 (sherwood oil: the .IR (NaCl) 3067,3036,2961,1760,1683,1266,1057,735 of acetone=160:1), 696cm
-1MSm/z:ESI
+, 267[M+Na]
+ESI
-, 243[m-1]
+ 1H NMR (CDCl
3) δ=5.21 (dd, J=42.5/10Hz, 2H), 5.82 (d, J=39.5Hz, 1H), 7.17～7.51 (m, 10H).
It is as shown in table 2 that the present invention adopts different hydroxy derivatives to be that raw material carries out the alcoholic hydroxyl fluorine derivatives of fluoro-reaction preparation:
Table 2: the fluoro result of various alcohol
Claims (10)
1, a kind of synthetic method of alcoholic hydroxyl fluorine derivatives, it is characterized in that: under organic amine and organic solvent existence condition, unite and use PBSF and TBAT to carry out fluoro-reaction, obtain the alcoholic hydroxyl fluorine derivatives of representing suc as formula 2 as the hydroxy derivatives of fluorination reagent and formula 1 expression.
In formula 1 and the formula 2: R
1, R
2Can be H independently of one another, alkyl, aromatic base or the alkyl that is substituted, aromatic base, the ether of aromatic base, tertiary amine, ester group, the two keys in β position are to unsettled trityl nitrogen of acid or oxygen base, α position carbonyl.
2, the synthetic method of a kind of alcoholic hydroxyl fluorine derivatives as claimed in claim 1 is characterized in that: described hydroxy derivatives is 1,2 grade of Fatty Alcohol(C12-C14 and C12-C18).
3, the synthetic method of a kind of alcoholic hydroxyl fluorine derivatives as claimed in claim 1 is characterized in that: described PBSF consumption is 1.5～2.5 times of equivalents of hydroxy derivatives.
4, the synthetic method of a kind of alcoholic hydroxyl fluorine derivatives as claimed in claim 1 is characterized in that: the consumption of described TBAT is 0.8～1.2 times of equivalent of hydroxy derivatives.
5, the synthetic method of a kind of alcoholic hydroxyl fluorine derivatives as claimed in claim 1 is characterized in that: temperature of reaction of the present invention is under the room temperature condition.
6, the synthetic method of a kind of alcoholic hydroxyl fluorine derivatives as claimed in claim 1 is characterized in that: feeding sequence of the present invention is followed successively by: pure and mild TBAT, amine, solvent, last PBSF.
7, the synthetic method of a kind of alcoholic hydroxyl fluorine derivatives as claimed in claim 1 is characterized in that: described organic solvent is non-proton and organic solvent that polarity is less.
8, the synthetic method of a kind of alcoholic hydroxyl fluorine derivatives as claimed in claim 7 is characterized in that: described organic solvent is selected from benzene, toluene, dimethylbenzene, aromatic hydrocarbons such as chlorobenzene; Tetrahydrofuran (THF), 2-methyltetrahydrofuran, ether, isopropyl ether, ethers such as tirethylene glycol dme; Methylene dichloride, 1, halogenated hydrocarbons such as 2-ethylene dichloride a kind of.
9, the synthetic method of a kind of alcoholic hydroxyl fluorine derivatives as claimed in claim 1 is characterized in that: described organic amine is the aliphatic hydrocarbon tertiary amine.
10, the synthetic method of a kind of alcoholic hydroxyl fluorine derivatives as claimed in claim 9, it is characterized in that: described organic amine is selected from triethylamine, triethylene diamine, diisopropyl methylamine, diisopropylethylamine, N-methyl piperidine, N, the N-dimethylcyclohexylamine, 1.8-diazabicylo (5.4.0) 11 hydrocarbon-7-alkene (DBU), 1.5-diazabicylo (4.3.0) ninth of the ten Heavenly Stems-5-alkene (DBN) a kind of.
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| CN107406356A (en) * | 2015-03-31 | 2017-11-28 | 关东电化工业株式会社 | The manufacture method of fluor alkaline, the separation of amidine alkali, recovery method and the application method for reclaiming amidine alkali |
| CN113874351A (en) * | 2019-05-24 | 2021-12-31 | 上海博璞诺科技发展有限公司 | Synthetic method of florfenicol |
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| CN107406356A (en) * | 2015-03-31 | 2017-11-28 | 关东电化工业株式会社 | The manufacture method of fluor alkaline, the separation of amidine alkali, recovery method and the application method for reclaiming amidine alkali |
| CN107245023A (en) * | 2017-01-05 | 2017-10-13 | 中国科学院上海有机化学研究所 | A kind of selective deoxofluorination reagent and method |
| CN107245023B (en) * | 2017-01-05 | 2019-08-16 | 中国科学院上海有机化学研究所 | A kind of selectivity deoxofluorination reagent and method |
| CN113874351A (en) * | 2019-05-24 | 2021-12-31 | 上海博璞诺科技发展有限公司 | Synthetic method of florfenicol |
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Application publication date: 20090701 |