CN105801530A - Synthetic method of 4-substituted chiral gamma-butyrolactone - Google Patents
Synthetic method of 4-substituted chiral gamma-butyrolactone Download PDFInfo
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- CN105801530A CN105801530A CN201610226192.7A CN201610226192A CN105801530A CN 105801530 A CN105801530 A CN 105801530A CN 201610226192 A CN201610226192 A CN 201610226192A CN 105801530 A CN105801530 A CN 105801530A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/26—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D307/30—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D307/32—Oxygen atoms
- C07D307/33—Oxygen atoms in position 2, the oxygen atom being in its keto or unsubstituted enol form
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- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
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Abstract
The invention relates to a synthetic method of 4-substituted chiral gamma-butyrolactone shown as a formula I. The cost is lower, the enantioselectivity is high, and the synthetic method has broad application prospect in synthesis of important biologically active compounds or key drug intermediates. The formula I is shown in the specification, wherein R is selected from C1-C6 linear or branched alkyl groups, C2-C8 linear or branched alkenyl-alkyl groups, C2-C8 linear or branched alkynyl-alkyl groups, 3-8-membered cycloaliphatic groups, aryl groups, heteroaryl groups and Ar(CH2)n-groups, Ar represents the aryl groups and the heteroaryl groups, and n ranges from 1 to 6.
Description
Technical field
The present invention relates to organic chemical synthesis field, be specifically related to as compound or the pass with particular organisms activity
The synthetic method of 4 substituted chiral gamma-butyrolactone compounds of key pharmaceutical intermediate.
Background technology
In the fields such as medicine, medical treatment, organic chemistry, the compound containing chiral gamma-butyrolactone structure occupies the heaviest
The status wanted.This is because the compound containing chiral gamma-butyrolactone often shows preferable biological activity, such as it is used for treating
The medicine pilocarpine of primary glaucoma, the medicine podophyllotoxin tincture etc. for the treatment of wart body all contain chiral gamma-butyrolactone knot
Structure.
It addition, as important pharmaceutical intermediate, chiral gamma-butyrolactone compounds also has extensively in pharmaceutical synthesis
Application.Such as a new generation antiepileptic Briviact(Brivaracetam, Bu Waxitan) synthesis just used 4 and taken
Chiral gamma-butyrolactone compounds (the R)-4-propyl group dihydrofuran-2(3H in generation)-one (Kenda, B. et al., J.
Med. Chem. 2004,47,530-549).
The medicine being the most such as clinically used for treating peripheral neuralgia and auxiliary therapy limitation partial seizure is general
In the synthesis of auspicious Bahrain and some other γ-aminobutyric acid (GABA) class reactive compound, also use chiral gamma-butyrolactone class
Compound is as intermediate (Belliotti, T. et al., J. Med. Chem. 2005,48,2294-2307), logical
Formula is as follows:
In view of chiral gamma-butyrolactone is not only important active group, and also have a wide range of applications in the synthesis of medicine,
Therefore, the synthetic method of research chiral gamma-butyrolactone compounds I just has great importance.
Comprehensive consulting literatures, finds that the representational synthetic method of chiral gamma-butyrolactone compound I mainly has following five
Bar route:
Document Kosugi, H.et al., J.Chem.Soc.Perkin Trans.I.1989,935-943 describes compound I's
Synthetic method, has used the most business-like chiral sulfoxide as starting material, has also used the most valuable in reaction in method
Rhodium catalyst and more malicious tin reagent, so this route industrial applications relatively difficult to achieve.
Document Chamberlin, R. et al., J. Org. Chem. 1993,58,2725-2737 reports with hands
Property oxazoline ketone and bromoacetyl chloride be starting material synthesis compound I route, this route steps is long, and wherein multistep needs low temperature bar
Part, comparatively laborious and operation is difficult to, and overall yield is relatively low, and the mercury reagent of severe toxicity is also used in final step, and environment is unfriendly, no
It is suitable for amplifying and produces.
Document Mukaiyama, T. et al., Chem Lett, 1980,645-638 build with chiral amino alcohol seven
Ring is that starting material carrys out synthesis of chiral gamma-butyrolacton I, has also used several seldom used reagent and has participated in reaction, and cost is the highest, uncomfortable
Together in actual industrial production.
Document Hughes, G. et al., J. Am. Chem. Soc. 2003,125,11253-11258 introduces
Synthetic route is shorter, builds chiral carbon by the method for asymmetry catalysis, and organic ligand cost is high, and asymmetry catalysis is put at batch
It is difficult to keep higher ee value time big, simultaneously because use heavy metal catalyst, product has heavy-metal residual unavoidably, and makees
During for medicine intermediate, need to strictly control beavy metal impurity, also can increase the development difficulty of synthesis technique.
Document Rudroff, F. et al., Adv. Synth. Catal. 2007,349,1,436 1444 reports
Route more succinct, but to use the biological enzyme agent of costliness, be not suitable for industrialized production.
Problem present in route is reported, the chiral gamma-butyrolactone synthesis work that the present inventor's design makes new advances in order to overcome
Skill route, and pass through its feasibility of experimental verification.New technology route has that starting material is easy to get, reaction yield is high, operation letter
Just, the advantage such as enantioselectivity is good, there is prospects for commercial application widely.
Summary of the invention
Technical scheme and content relate to 4 substituted chiral gamma-butyrolactone compounds shown in a kind of following formula I
Synthetic method.
4 substituted chiral gamma-butyrolacton compounds of the present invention, can be as reactive compound, can also be as weight
The pharmaceutical intermediate wanted, shown in formula I:
Wherein, R type, S type it are configured as shown in * position；
R selected from C1-C6 straight or branched alkyl, C2-C8 straight or branched allylic alkylation, C2-C8 straight or branched alkynes alkyl,
3-8 unit alicyclic group, aryl, heteroaryl, Ar (CH2) n-group, wherein, Ar represents aryl, heteroaryl, n=1-6.
The synthesis technique of above-mentioned chiral gamma-butyrolactone compounds is as follows:
Wherein:
* R type, S type it are configured as shown in position；
R selected from C1-C6 straight or branched alkyl, C2-C8 straight or branched allylic alkylation, C2-C8 straight or branched alkynes alkyl,
3-8 unit alicyclic group, aryl, heteroaryl, Ar (CH2) n-group, wherein, Ar represents aryl, heteroaryl, n=1-6；
R1Selected from benzyl, trimethyl is silica-based, t-Butyldimethylsilyl, tert-butyl diphenyl are silica-based, 2-(trimethylsilyl) second
Oxygen methyl, pi-allyl, methyl, ethyl, isopropyl, methoxyl methyl, 2-methoxvethoxvmethvl；
R2Selected from methyl, ethyl, isopropyl, the tert-butyl group.
The synthesis of above-mentioned 4 substituted chiral gamma-butyrolactone compounds, comprises the following specific steps that:
(1) preparation of intermediate compound III
Compound II stirs in a solvent with sodium nitrite, bromide reagent, the most post-treated obtains compound III；
(2) preparation of midbody compound IV
Compound III stirs in a solvent with reducing agent, the most post-treated obtains compound IV；
(3) preparation of midbody compound V
Compound IV, hydroxy protecting agent, alkali are joined in solvent, stirring reaction, the most post-treated right with height
Reflect selectivity and obtain compound V；
(4) preparation of midbody compound VI
Compound V, malonate, alkali are joined in solvent, stirring reaction, the most post-treated select with high mapping
Property obtains compound VI；
(5) preparation of chiral gamma-butyrolactone I
Compound VI and decarboxylation reagent reacting, can obtain decarboxylatable compound VII, and VII takes off hydroxyl under Deprotection reagent effect
Protection group, can obtain compound VIII, VIII cyclization under the effect of acid or alkali, available chiral gamma-butyrolactone I；Also may select
Suitably acid reagent reacts in a solvent with VI, directly generates chiral gamma-butyrolactone I.
In the synthetic route of 4 substituted chiral gamma-butyrolactones of the present invention, step (1) described bromide reagent selects
From hydrobromic acid, bromine, N-bromosuccinimide, tetrabutyl tribromide ammonium, wherein preferred hydrobromic acid.
In the synthetic route of 4 substituted chiral gamma-butyrolactones of the present invention, step (2) described reducing agent is selected from
Diborane, borane complex, sodium borohydride, potassium borohydride, lithium borohydride, Lithium Aluminium Hydride, wherein preferred lithium borohydride.
In the synthetic route of 4 substituted chiral gamma-butyrolactones of the present invention, step (5) described decarboxylation reagent, de-
Used by protection group reagent or cyclization, acid is selected from hydrochloric acid, dust technology, sulphuric acid, trifluoroacetic acid, glacial acetic acid, p-methyl benzenesulfonic acid, benzene sulphur
Acid, Fluohydric acid., hydrobromic acid, tetrabutyl ammonium fluoride.
In the synthetic route of 4 substituted gamma-butyrolactons of chirality of the present invention, described alkali is selected from 4-dimethylamino
Pyridine, triethylamine, pyridine, diisopropyl ethyl amine, 1,4-diazabicyclo [2.2.2] octane (DABCO), 1,8-diaza are double
Ring [5.4.0] 11 carbon-7-alkene (DBU), imidazoles, sodium hydride, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, Feldalat NM,
Sodium ethylate, potassium tert-butoxide, n-BuLi, tert-butyl lithium, LHMDS (LiHMDS), the silica-based amido of hexamethyl two
Sodium (NaHMDS), potassium hexamethyldisilazide (KHMDS).The wherein preferred sodium hydride of alkali used by step (4).
In the synthetic route of 4 substituted chiral gamma-butyrolactones of the present invention, described solvent selected from oxolane,
Acetonitrile, N,N-dimethylformamide, N-Methyl pyrrolidone, 1,4-dioxane, dichloromethane, chloroform, methyl tertiary butyl ether(MTBE),
Ether, water, methanol, ethanol, glacial acetic acid.Wherein the preferred water of step (1) solvent for use is (it practice, originally just contain in hydrobromic acid
Water), the preferred oxolane of step (2) solvent for use.
Embodiment
The preparation of R propyl group dihydrofuran-2 (3H)-one
The first step: (R)-2-bromine valeric acid
Under ice-water bath, (R)-2-aminovaleric acid (11.7 g, 100 mmol) is added hydrobromic acid (120 g, 48%) and water (50
ML) in, stirring.Add sodium nitrite (11.0 g, 160 mmol), continue stirring 1 h under ice-water bath, remove ice-water bath, room temperature
Lower reaction is overnight.In reactant liquor, saturated aqueous sodium carbonate it is slowly added dropwise while stirring, until reactant liquor is in partially under ice-water bath
Acidity, dichloromethane (100 mL*3) extracts, and merges organic facies, and anhydrous sodium sulfate is dried, and concentrating under reduced pressure removes organic facies,
(R)-2-bromine valeric acid 14.7 g (81.2 mmol, yield 81.2%)；MS (M-1 )- = 179.0, 181.0。
Second step: (R)-2-bromine n-pentyl-1-alcohol
(R)-2-bromine valeric acid (14.0g, 77.3 mmol) is dissolved in dry oxolane (150 mL), drips under ice-water bath
Diborane tetrahydrofuran solution (116 mL, 116.0 mmol, 1M), after stirring 1 h, recovers to room temperature to continue stirring 2 h.Frozen water
Bath downhill reaction liquid drips unsaturated carbonate potassium solution (100 mL), drips and finish, continue stirring 10 min under room temperature, filter, decompression
Concentrating and remove solvent, residue obtains (R)-2-bromine n-pentyl-1-through silica gel column chromatography (dichloromethane: methanol=10:1) purification
Alcohol 12.0 g (72.0 mmol, yield 93.2%).1H NMR (400 MHz, CDCl3):δ4.11-4.18 (m, 1H),
3.71-3.83 (m, 2H), 2.45 (brs, 1H), 1.78-1.84 (m, 2H), 1.36-1.63 (m, 2H), 0.92
(t, J = 7.2 Hz, 3H); MS (M+1)+ = 167.0, 169.0。
3rd step: (R)-(2-bromine amoxy) (tert-butyl group) dimethylsilane
Nitrogen protection under, by (R)-2-bromine n-pentyl-1-alcohol (10.0 g, 60.0 mmol), imidazoles (12.2 g, 180.0
Mmol) it is dissolved in dichloromethane (150 mL), is cooled to-10 DEG C, and dropping tert-butyl chloro-silicane (13.6 g, 90.0
Mmol).Dripping and finish, be stirred overnight, be filtered to remove insoluble matter under room temperature, filtrate is successively with 10% aqueous citric acid solution (100 mL*2)
Washing with saturated aqueous common salt (100 mL), anhydrous sodium sulfate is dried, and concentrating under reduced pressure removes solvent, obtains (R)-(2-bromine amoxy)
(tert-butyl group) dimethylsilane 16.2 g(57.8 mmol, yield 96.3%).1H NMR (400 MHz, CDCl3):δ3.89
(m, 1H), 3.40 (m, 1H), 1.78-1.84 (m, 2H), 1.36-1.63 (m, 2H), 0.99 (s, 9H),
0.92 (t, J=7.2 Hz, 3H), 0.10 (s, 6H); MS (M+1)+ = 281.0, 283.0。
4th step: (R)-2-(1-(tertiary butyl dimethyl Si base) amyl-2-yl) diethyl malonate
Under nitrogen protection, sodium hydride (2.2 g, 55.0 mmol, 60%) is suspended in DMF (30 mL),
The most slowly drip diethyl malonate (8.8 g, 55.0 mmol) under ice-water bath, drip and finish, under room temperature, continue stirring 1 h,
The DMF (50 of dropping (R)-(2-bromine amoxy) (tert-butyl group) dimethylsilane (14.0 g, 50.0 mmol)
ML) solution, continues stirring, and TLC monitoring is until after reaction completely, (100 mL) cancellation that adds water is reacted, dichloromethane (200 mL*
2) extraction, merges organic facies, and organic facies saturated aqueous common salt (200 mL*2) washs, and is dried through anhydrous sodium sulfate, removes under reduced pressure
Solvent obtains (R)-2-(1-(tertiary butyl dimethyl Si base) amyl-2-yl) diethyl malonate 15.5 g(43.0 mmol, yield
86.0%).
5th step: (R)-4-propyl group dihydrofuran-2 (3H)-one
(R)-2-(1-(tertiary butyl dimethyl Si base) amyl-2-yl) diethyl malonate (15.0 g, 41.6 mmol) is dissolved in
Glacial acetic acid (100mL), with the mixed solution of concentrated hydrochloric acid (100mL, 36.5%), is heated to back flow reaction 24h, is down to room temperature and continues
Stirring 4 h, concentrating under reduced pressure removes partial solvent, and ethyl acetate (100 mL*3) extracts, organic facies saturated aqueous common salt (100
ML*2) washing, anhydrous sodium sulfate is dried, filter, concentrating under reduced pressure remove organic solvent, residue through silica gel column chromatography (normal hexane:
Ethyl acetate=5:1) purification obtains (R)-4-propyl group dihydrofuran-2 (3H)-one 3.7 g(29.5 mmol, yield 70.9%,
Ee=97.2%).[α]D= +6.9° (c = 1.30, EtOH)；1H NMR (400 MHz, CDCl3):δ4.43 (dd,
J1=8.8 Hz, J2 = 7.6 Hz, 1H), 3.93 (dd, J1=8.8 Hz, J2 = 7.6 Hz, 1H), 2.69-
2.54 (m, 2H), 2.26-2.14 (m, 1H), 1.49-1.28 (m, 4H), 0.96 (t, J = 7.3 Hz, 3H);
MS (M+1)+ = 129.1。
Claims (7)
1. a synthetic method for the substituted chiral gamma-butyrolactone in 4 shown in following formula I,
Wherein, R type, S type it are configured as shown in * position；
R selected from C1-C6 straight or branched alkyl, C2-C8 straight or branched allylic alkylation, C2-C8 straight or branched alkynes alkyl,
3-8 unit alicyclic group, aryl, heteroaryl, Ar (CH2) n-group, wherein, Ar represents aryl, heteroaryl, n=1-6.
2. the synthetic method of 4 substituted chiral gamma-butyrolactones described in claim 1, it is characterised in that comprise the steps:
(1) preparation of intermediate compound III
Compound II stirs in a solvent with sodium nitrite, bromide reagent, the most post-treated obtains compound III；
(2) preparation of midbody compound IV
Compound III stirs in a solvent with reducing agent, the most post-treated obtains compound IV；
(3) preparation of midbody compound V
Compound IV, hydroxy protecting agent, alkali are joined in solvent, stirring reaction, the most post-treated right with height
Reflect selectivity and obtain compound V；
(4) preparation of midbody compound VI
Compound V, malonate, alkali are joined in solvent, stirring reaction, the most post-treated select with high mapping
Property obtains compound VI；
The preparation of (5) 4 substituted chiral gamma-butyrolactone I
Compound VI and decarboxylation reagent reacting, can obtain decarboxylatable compound VII, and VII takes off hydroxyl under Deprotection reagent effect
Protection group, can obtain compound VIII, VIII cyclization under the effect of acid or alkali, available chiral gamma-butyrolactone I；Also may select
Suitably acid reagent reacts in a solvent with VI, directly generates chiral gamma-butyrolactone I.
The synthetic method of 4 substituted chiral gamma-butyrolactones the most according to claim 2, it is characterised in that step (1) institute
State bromide reagent selected from hydrobromic acid, bromine, N-bromosuccinimide, tetrabutyl tribromide ammonium.
The synthetic method of 4 substituted chiral gamma-butyrolactones the most according to claim 2, it is characterised in that step (2) institute
State reducing agent selected from diborane, borane complex, sodium borohydride, potassium borohydride, lithium borohydride, Lithium Aluminium Hydride.
The synthetic method of 4 substituted chiral gamma-butyrolactones the most according to claim 2, it is characterised in that step (5) institute
State acid used by decarboxylation reagent, Deprotection reagent or cyclization selected from hydrochloric acid, dust technology, sulphuric acid, trifluoroacetic acid, glacial acetic acid, to first
Base benzenesulfonic acid, benzenesulfonic acid, Fluohydric acid., hydrobromic acid, tetrabutyl ammonium fluoride.
The synthetic method of 4 substituted chiral gamma-butyrolactones the most according to claim 2, it is characterised in that described alkali selects
From 4-dimethylaminopyridine, triethylamine, pyridine, diisopropyl ethyl amine, 1,4-diazabicyclo [2.2.2] octane
(DABCO), 1,8-diazabicyclo [5.4.0] 11 carbon-7-alkene (DBU), imidazoles, sodium hydride, sodium hydroxide, potassium hydroxide,
Sodium carbonate, potassium carbonate, Feldalat NM, Sodium ethylate, potassium tert-butoxide, n-BuLi, tert-butyl lithium, LHMDS
(LiHMDS), sodium hexamethyldisilazide (NaHMDS), potassium hexamethyldisilazide (KHMDS).
The synthetic method of 4 substituted chiral gamma-butyrolactones the most according to claim 2, it is characterised in that described solvent
Selected from oxolane, acetonitrile, N,N-dimethylformamide, N-Methyl pyrrolidone, 1,4-dioxane, dichloromethane, chloroform,
Methyl tertiary butyl ether(MTBE), ether, water, methanol, ethanol, glacial acetic acid.
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107759539A (en) * | 2017-11-14 | 2018-03-06 | 安徽华胜医药科技有限公司 | A kind of new method for preparing butyrolactone derivative |
| CN108203419A (en) * | 2016-12-19 | 2018-06-26 | 浙江京新药业股份有限公司 | The preparation method of Bu Waxitan intermediates |
| CN109553595A (en) * | 2017-09-27 | 2019-04-02 | 上虞京新药业有限公司 | A kind of Preparation Method And Their Intermediate of chiral gamma-butyrolactone |
| WO2019242692A1 (en) | 2018-06-22 | 2019-12-26 | 福建海西新药创制有限公司 | Compound and use thereof in synthesis of brivaracetam intermediate and crude drug |
| CN113125585A (en) * | 2019-12-30 | 2021-07-16 | 成都百裕制药股份有限公司 | Method for detecting R-4-propyl-dihydrofuran-2-ketone or/and related substances thereof |
| CN113717132A (en) * | 2021-08-31 | 2021-11-30 | 珠海润都制药股份有限公司 | Key intermediate of antiepileptic drug and preparation method thereof |
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Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108203419A (en) * | 2016-12-19 | 2018-06-26 | 浙江京新药业股份有限公司 | The preparation method of Bu Waxitan intermediates |
| CN109553595A (en) * | 2017-09-27 | 2019-04-02 | 上虞京新药业有限公司 | A kind of Preparation Method And Their Intermediate of chiral gamma-butyrolactone |
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| WO2019242692A1 (en) | 2018-06-22 | 2019-12-26 | 福建海西新药创制有限公司 | Compound and use thereof in synthesis of brivaracetam intermediate and crude drug |
| US11247977B2 (en) | 2018-06-22 | 2022-02-15 | Fujian Haixi Pharmaceuticals Co., Ltd. | Compound and use thereof in synthesis of brivaracetam intermediate and crude drug |
| CN113125585A (en) * | 2019-12-30 | 2021-07-16 | 成都百裕制药股份有限公司 | Method for detecting R-4-propyl-dihydrofuran-2-ketone or/and related substances thereof |
| CN113125585B (en) * | 2019-12-30 | 2022-05-24 | 成都百裕制药股份有限公司 | Method for detecting R-4-propyl-dihydrofuran-2-ketone or/and related substances thereof |
| CN113717132A (en) * | 2021-08-31 | 2021-11-30 | 珠海润都制药股份有限公司 | Key intermediate of antiepileptic drug and preparation method thereof |
| CN113717132B (en) * | 2021-08-31 | 2023-03-03 | 珠海润都制药股份有限公司 | Key intermediate of antiepileptic drug and preparation method thereof |
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