CN102557990A - Preparation method for (4-substituted amide)-2-cyclopentene-1-carboxylate raceme and single enantiomer thereof - Google Patents

Preparation method for (4-substituted amide)-2-cyclopentene-1-carboxylate raceme and single enantiomer thereof Download PDF

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CN102557990A
CN102557990A CN2011101033615A CN201110103361A CN102557990A CN 102557990 A CN102557990 A CN 102557990A CN 2011101033615 A CN2011101033615 A CN 2011101033615A CN 201110103361 A CN201110103361 A CN 201110103361A CN 102557990 A CN102557990 A CN 102557990A
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安荣昌
王伟华
董学军
蒋胜力
蔡振伟
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Aifon Zhiyuan (Kaiyuan) Pharmaceutical Co. Ltd.
Shanghai Hongbo Zhiyuan pharmaceutical Limited by Share Ltd
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KAIYUAN HENGTAI PHARMA CO Ltd
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Abstract

The invention relates to a novel preparation method for (4-substituted amide)-2-cyclopentene-1-carboxylate raceme and single enantiomer thereof, and the method is suitable for industrial production. According to the invention, an electron-withdrawing protective group is introduced to N of raceme or single isomer of 2-azabicylo-[2.2.1]hept-5-ene-3-one, and then ring-opening is carried out in a mild alkaline aqueous solution or alcoholic solution so as to obtain (4-substituted amide)-2-cyclopentene-1-carboxylate with corresponding configuration.

Description

The preparation method of (4-substituted amide)-2-cyclopentenes-1-carboxylicesters racemic modification and single enantiomer thereof
Technical field
The invention belongs to the organic synthesis field, particularly relate to the new preparation process that (4-substituted amide)-2-cyclopentenes-1-carboxylicesters racemic modification and single enantiomer isomer thereof are fit to suitability for industrialized production, belong to chemical pharmacy field.
Background technology
(4-substituted amide)-2-cyclopentenes-the 1-carboxylic acid ester compound is important medicine intermediate, can be used for synthetic multiple substituted cyclopentane verivate, like treatment and the RWJ 270201 of flu-prevention virus and other medicine, has very big marketable value.
Being used for the domestic method of preparation (4-substituted amide)-2-cyclopentenes-1-carboxylicesters racemic modification and single enantiomer isomer thereof is so that 2-azabicyclic [2.2.1] heptan-5-alkene-3-ketone is raw material, at strong acid condition such as SOCl 2Or open loop under the condition of feeding hydrogen chloride gas.Though this method yield is higher, in Industrial processes heat release violent, strong to equipment corrosion, processing safety is poor, need amplify production technique to it and further optimize.
People such as Abe Takumi are describing a kind of open-loop method in the document (Heterocycles, 75 (12), 2931-2936,2008): earlier on 2-azabicyclic [2.2.1] heptan-5-alkene-3-ketone ring, introduce Boc protection base, then with PhB (OH) 2/ RhCl (COD) 2The open loop of/KOH system.But this method must be carried out under conditions such as high temperature microwave, is not suitable for industrial production.
Summary of the invention
To the defective in the above-mentioned field, the present invention introduces the electron withdrawing group group earlier so that 2-azabicyclic [2.2.1] heptan-5-alkene-3-ketone ring is a raw material on N; Open loop in alkaline aqueous solution or alcoholic solution then, reaction conditions is gentle, and yield is high; Convenient post-treatment has the advantage of industrial amplification production.
The present invention relates to the cyclopentenes of (4-substituted amide)-2-shown in the structural formula (I)-1-carboxylicesters racemic modification preparation method,
Figure BSA00000480439100021
R wherein 1Be hydrogen, alkane (oxygen) base, cycloalkanes (oxygen) base, virtue (oxygen) base, aralkyl (oxygen) base, R 2Be hydrogen; Alkyl, naphthenic base, aryl and aralkyl; It is characterized in that; The open loop under basic soln of compound shown in the employing formula (III) obtains, and said basic soln can be the aqueous solution or the alcoholic solution of alkali-metal oxyhydroxide, carbonate, supercarbonate, perhaps is the straight-chain paraffin of C1-C6 or the sodium alkoxide of naphthenic hydrocarbon, the alcoholic solution of potassium alcoholate.
Figure BSA00000480439100022
Its Chinese style (III) is passed through compound and R shown in the formula II 1C (=O) OC (=O) R 3Or R 1C (O) X reaction obtains, wherein R 3Be hydrogen, alkane (oxygen) base, cycloalkanes (oxygen) base, virtue (oxygen) base, aralkyl (oxygen) base; X can be Cl, Br.
The preparation method of compound shown in the structural formula IV,
Figure BSA00000480439100024
R wherein 1Be hydrogen, alkane (oxygen) base, cycloalkanes (oxygen) base, virtue (oxygen) base, aralkyl (oxygen) base, R 2Be hydrogen; Alkyl; Naphthenic base, aryl and aralkyl is characterized in that the compound open loop in basic soln shown in the formula (VI) is obtained; Said basic soln can be the aqueous solution or the alcoholic solution of alkali-metal oxyhydroxide, carbonate, supercarbonate, perhaps is the straight-chain paraffin of C1-C6 or the sodium alkoxide of naphthenic hydrocarbon, the alcoholic solution of potassium alcoholate.
Figure BSA00000480439100031
Its Chinese style (VI) is passed through compound and R shown in the formula V 1C (=O) OC (=O) R 3Or R 1C (O) X reaction obtains, wherein R 3Be hydrogen, alkane (oxygen) base, cycloalkanes (oxygen) base, virtue (oxygen) base, aralkyl (oxygen) base; X can be Cl, Br.
Figure BSA00000480439100032
The preparation method of compound shown in the structural formula VII,
Figure BSA00000480439100033
R wherein 1Be hydrogen, alkane (oxygen) base, cycloalkanes (oxygen) base, virtue (oxygen) base, aralkyl (oxygen) base, R 2Be hydrogen; Alkyl; Naphthenic base, aryl and aralkyl is characterized in that the open loop in basic soln of the compound I X shown in the formula V is obtained; Said basic soln can be the aqueous solution or the alcoholic solution of alkali-metal oxyhydroxide, carbonate, supercarbonate, perhaps is the straight-chain paraffin of C1-C6 or the sodium alkoxide of naphthenic hydrocarbon, the alcoholic solution of potassium alcoholate.
Figure BSA00000480439100034
Its Chinese style (IX) is passed through compound and R shown in the formula VIII 1C (=O) OC (=O) R 3Or R 1C (O) X reaction obtains, wherein R 3Be hydrogen, alkane (oxygen) base, cycloalkanes (oxygen) base, virtue (oxygen) base, aralkyl (oxygen) base; X can be Cl, Br.
Said ring-opening reaction is with formula (I), (IV) or the compound (VII), with alkali in the normal basic soln of 0.03-0.08 in-10-0 ℃ reaction.
R wherein 1, R 3Be C1-C7 alkyl, naphthenic base or alkoxyl group, R 2Alkyl or cycloalkyl for C1-C7.
R 1Be tert.-butoxy, R 2Be methyl, X is Cl.
Basic soln wherein is the methanol solution of sodium methylate.
Adopt the present invention through going up electrophilic blocking group of introducing at the racemic modification of compound (II) or " N " of individual isomer, open loop is prepared into compound I under comparatively gentle alkaline condition then.Compound I (4-substituted amide)-2-cyclopentenes-1-carboxylic acid ester compound is important medicine intermediate; Can be used for synthetic multiple substituted cyclopentane verivate; Like the RWJ 270201 of treatment and flu-prevention virus, and other medicine, very big marketable value had.
With 2-azabicyclic shown in the formula II [2.2.1] heptan-5-alkene-3-ketone and R 1C (=O) OC (=O) R 3Or R 1C (O) X reaction obtains compound III.
Figure BSA00000480439100041
When selecting R 1C (=O) OC (=O) R 3When reacting with II, R 1Preferential various alkoxyl groups or the aryloxy selected replaces, like: tert.-butoxy, phenoxy, to methylphenoxy, p-nitrophenyl oxygen base etc., wherein R 3Can be hydrogen, alkane (oxygen) base, cycloalkanes (oxygen) base, aryl, aralkyl (oxygen) base etc.When selecting R 1When C (O) X and II reaction, R 1The various alkyl or aryls of preferential selection replace, and X can be Cl, Br.
With compound III open loop under basic soln, obtain compound I.
Figure BSA00000480439100042
Basic soln wherein can be the aqueous solution or the alcoholic solution of various alkali-metal oxyhydroxide, carbonate, supercarbonate, also can be the sodium alkoxide of 1 carbosilane unit to 6 carbosilane unit straight-chain paraffin or naphthenic hydrocarbon, the alcoholic solution of potassium alcoholate; Preferentially select the sodium alkoxide of straight-chain paraffin or naphthenic hydrocarbon, the alcoholic solution of potassium alcoholate in the present invention, like the methanol solution of sodium methylate, the ethanolic soln of sodium ethylate etc.
In this patent, unless otherwise mentioned:
" alkyl " comprises the straight chain and the side chain of 1-8 carbon atom, is good with 1-3 carbon atom.Alkyl can comprise for example methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, sec.-butyl, the tertiary butyl, amyl group etc.
The saturated mono ring structure of 3-8 carbon atom of " naphthenic base " expression, cyclopropyl for example, cyclobutyl, cyclopentyl, cyclohexyl etc.
The non-replacement carbon family aromatic group of " aryl " expression, phenyl for example, naphthyls etc. are good with phenyl.
" aralkyl " expression contains the alkyl of the substituted 1-6 of containing of an aryl carbon atom, benzyl for example, styroyl etc.
Unless otherwise mentioned, the substituting group on aryl and the aralkyl is one or more halogens among this paper, is good with one or two.
A kind of in preferred implementation of the present invention, said process is used to prepare R 1Be the tertiary butyl, R 2Compound (1) for methyl.
The present invention relates to shown in scheme 1, prepare the method for compound 3:
Scheme 1
Figure BSA00000480439100051
Specifically, compound 1 generates compound 2 with tert-Butyl dicarbonate and alkali reaction, and compound (2) is a known compound, or available currently known methods makes; Said alkali is the 4-Dimethylamino pyridine, and consumption 0.008-0.01 equivalent is good; Temperature of reaction is that room temperature is good.
The methanol solution of compound (2) being cooled to-10-0 ℃, is good with-5 ℃, reacts with 0.03-0.08 equivalent (is good with 0.05 equivalent) sodium methylate then.After having reacted, at low temperatures rapidly with pH regulator to 3-5 (is good with 4-5).
Description of drawings
Fig. 1 is based on high performance liquid chromatography detection figure of the present invention
Testing conditions:
Post: CHIRALCELR OD-H.150*4.6mm
Moving phase: hexane/IPA=98/2
Flow velocity: 0.8ml/ minute
Temperature: 30 ℃
Detection time: 35 minutes
Add-on: 10 μ l
Test item: UV
Wavelength: 220nm
Wherein A is the histogram of expression peak area, and B is the peak-data chart of corresponding diagram A.
Embodiment
The purpose of following examples be the explanation and non-limiting.
Embodiment 1
(1) (1R, 4S) N-tertbutyloxycarbonyl-2-azabicyclo [2.2.1] heptan-5-alkene-3-ketone (2)
Under the room temperature successively will (1R, 4S)-2-azabicyclic [2.2.1] heptan-5-alkene-3-ketone (1) (4.5g, 0.04mol); (43.8mg 0.36mmol) is dissolved among the anhydrous THF of 45mL (anhydrous tetrahydro furan) DMAP, stirs slowly to drip tert-Butyl dicarbonate (10.8g down; 0.05mol); Add stirred overnight under the room temperature of back, the pressure reducing and steaming solvent gets yellow solid.Solid substance is suspended in the 30mL normal hexane, and making beating was stirred 1 hour, suction filtration, and normal hexane washing 2-3 time, vacuum-drying gets the faint yellow solid product.
Output: 5.2g.Yield: 96%.MS(M+1)：210。HPLC purity: 99.7% (220nm), optical purity:＞99% (the de value, 220nm).
1H?NMR(400MHz，CDCl 3)：δ6.91(dd，J＝5.3，2.2Hz，1H)，6.76-6.56(m，1H)，5.04-4.88(m，1H)，3.51-3.30(m，1H)，2.36(dt，J＝8.5，1.6Hz，1H)，2.16(dt，J＝8.5，1.5Hz，1H)，1.52(s，9H).
(2)
By (1R, 4S) N-tertbutyloxycarbonyl-2-azabicyclo [2.2.1] heptan-5-alkene-preparation of 3-ketone (1S, 4R) N-tertbutyloxycarbonyl-4-amino-2-cyclopentenes-1-carboxylate methyl ester (3)
With compound (1R, 4S)-(-)-the 2-tertbutyloxycarbonyl-2-azabicyclo [2.2.1] heptan-(7.3g 0.035mol) is dissolved in the 70mL methyl alcohol 5-alkene-3-ketone; System is bathed with cryosel and is cooled to-10 ℃, stirs the methanol solution (17.5mL, the 1.75mmol that slowly drip sodium methylate down; 0.1mol/L); Holding temperature-10-0 ℃, add back continuation stir about under this temperature and dripped Hydrogen chloride (2N) and regulate the pH value to reacting completely in 1 hour to 4-5.Add 100mL water and 200mL ETHYLE ACETATE then successively, stirred 10 minutes, tell organic phase; Water merges organic phase with ETHYLE ACETATE (100mL * 2) extraction, washs with saturated aqueous common salt (200mL); Concentrate behind the anhydrous sodium sulfate drying, get the yellow oily product liquid.
Output: 8.0g, yield: 95%.MS(M+1)：242。HPLC purity: 97.1% (220nm).
Optical purity:＞99% (the de value, 220nm).As shown in Figure 1.
1H?NMR(400MHz，CDCl3)：δ6.03-5.74(m，2H)，5.13-4.86(m，1H)，4.85-4.70(m，1H)，3.71(s，3H)，3.48(dd，J＝8.1，3.9Hz，1H)，2.51(dt，J＝13.9，8.5Hz，1H)，1.86(dt，J＝13.9，4.1Hz，1H)，1.44(s，9H)。

Claims (10)

1. the cyclopentenes of (4-substituted amide)-2-shown in the structural formula (I)-1-carboxylicesters racemic modification preparation method,
Figure FSA00000480439000011
R wherein 1Be hydrogen, alkane (oxygen) base, cycloalkanes (oxygen) base, virtue (oxygen) base, aralkyl (oxygen) base, R 2Be hydrogen; Alkyl, naphthenic base, aryl and aralkyl; It is characterized in that; The open loop under basic soln of compound shown in the employing formula (III) obtains, and said basic soln is the aqueous solution or the alcoholic solution of alkali-metal oxyhydroxide, carbonate, supercarbonate, perhaps is the straight-chain paraffin of C1-C6 or the sodium alkoxide of naphthenic hydrocarbon, the alcoholic solution of potassium alcoholate.
Figure FSA00000480439000012
2. preparation method according to claim 1, its Chinese style (III) is passed through compound and R shown in the formula II 1C (=O) OC (=O) R 3Or R 1C (O) X reaction obtains, wherein R 3Be hydrogen, alkane (oxygen) base, cycloalkanes (oxygen) base, virtue (oxygen) base or aralkyl (oxygen) base; X is Cl or Br.
Figure FSA00000480439000013
3. the preparation method of compound shown in the structural formula IV,
Figure FSA00000480439000014
R wherein 1Be hydrogen, alkane (oxygen) base, cycloalkanes (oxygen) base, virtue (oxygen) base and aralkyl (oxygen) base, R 2Be hydrogen; Alkyl; Naphthenic base, aryl and aralkyl is characterized in that the compound open loop in basic soln shown in the formula (VI) is obtained; Said basic soln can be the aqueous solution or the alcoholic solution of alkali-metal oxyhydroxide, carbonate, supercarbonate, perhaps is the straight-chain paraffin of C1-C6 or the sodium alkoxide of naphthenic hydrocarbon, the alcoholic solution of potassium alcoholate.
Figure FSA00000480439000021
4. preparation method according to claim 3, its Chinese style (VI) is passed through compound and R shown in the formula V 1C (=O) OC (=O) R 3Or R 1C (O) X reaction obtains, wherein R 3Be hydrogen, alkane (oxygen) base, cycloalkanes (oxygen) base, virtue (oxygen) base and aralkyl (oxygen) base; X is Cl or Br.
Figure FSA00000480439000022
5. the preparation method of compound shown in the structural formula VII,
Figure FSA00000480439000023
R wherein 1Be hydrogen, alkane (oxygen) base, cycloalkanes (oxygen) base, virtue (oxygen) base, aralkyl (oxygen) base, R 2Be hydrogen; Alkyl; Naphthenic base, aryl and aralkyl is characterized in that the open loop in basic soln of the compound I X shown in the formula V is obtained; Said basic soln can be the aqueous solution or the alcoholic solution of alkali-metal oxyhydroxide, carbonate or supercarbonate, perhaps is straight-chain paraffin or the sodium alkoxide of naphthenic hydrocarbon or the alcoholic solution of potassium alcoholate of C1-C6.
Figure FSA00000480439000031
6. preparation method according to claim 5, its Chinese style (IX) is passed through compound and R shown in the formula VIII 1C (=O) OC (=O) R 3Or R 1C (O) X reaction obtains, wherein R 3Be hydrogen, alkane (oxygen) base, cycloalkanes (oxygen) base, virtue (oxygen) base and aralkyl (oxygen) base; X is C1 or Br.
Figure FSA00000480439000032
7. according to the arbitrary described preparation method of claim 1-6, said ring-opening reaction is with formula (I), (IV) or the compound (VII), with alkali in the normal basic soln of 0.03-0.08 in-10-0 ℃ reaction.
8. according to claim 2,4 or 6 described preparation method, wherein R 1, R 3Be C1-C7 alkyl, naphthenic base or alkoxyl group, R 2Alkyl or cycloalkyl for C1-C7.
9. preparation method according to claim 8, R 1Be tert.-butoxy, R 2Be methyl, X is Cl.
10. preparation method according to claim 9, basic soln wherein is the methanol solution of sodium methylate.
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US20040265985A1 (en) * 1996-05-30 2004-12-30 Christine Bernegger-Egli Process for the preparation of amino alcohols and derivatives thereof
EP1502914A1 (en) * 1997-05-13 2005-02-02 Lonza AG Process for the preparation of 1-amino-4-(hydroxymethyl)-2-cyclopentene derivatives
CN101284811A (en) * 2008-06-11 2008-10-15 常州恩滋生物科技有限公司 Synthetic method for chiral carbocyclic ring intermediate of abacavir
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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4950758A (en) * 1988-01-20 1990-08-21 Regents Of The University Of Minnesota Optically-active isomers of dideoxycarbocyclic nucleosides
US20040265985A1 (en) * 1996-05-30 2004-12-30 Christine Bernegger-Egli Process for the preparation of amino alcohols and derivatives thereof
EP1502914A1 (en) * 1997-05-13 2005-02-02 Lonza AG Process for the preparation of 1-amino-4-(hydroxymethyl)-2-cyclopentene derivatives
CN101284811A (en) * 2008-06-11 2008-10-15 常州恩滋生物科技有限公司 Synthetic method for chiral carbocyclic ring intermediate of abacavir
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《HETEROCYCLES》 20081231 Takumi Abe等 RHODIUM-CATALYZED ARYLATION OF2-AZABICYCLO[2.2.1]HEPT-5-EN-3-ONE WITH ARYLBORONIC ACIDS UNDER MICROWAVE IRRADIATION 第2931-2936页 2、4、6-9 第75卷, 第12期 *
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