CN110357821A - A kind of method of the trans- carbocyclic ring pyrimidine nucleoside of synthesis of chiral - Google Patents
A kind of method of the trans- carbocyclic ring pyrimidine nucleoside of synthesis of chiral Download PDFInfo
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- CN110357821A CN110357821A CN201910663944.XA CN201910663944A CN110357821A CN 110357821 A CN110357821 A CN 110357821A CN 201910663944 A CN201910663944 A CN 201910663944A CN 110357821 A CN110357821 A CN 110357821A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B53/00—Asymmetric syntheses
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
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- C07D239/54—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
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- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
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- C07B2200/07—Optical isomers
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- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
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- C07B2200/09—Geometrical isomers
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- C—CHEMISTRY; METALLURGY
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- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Abstract
The invention discloses a kind of methods of the trans- carbocyclic ring pyrimidine nucleoside of synthesis of chiral, belong to the field of asymmetric synthesis in organic chemistry.It is raw material with racemic ' alpha '-pyrimidine cyclic ketones 1, in the presence of chiral ruthenium catalyst, formic acid and triethylamine is added, tool is obtained after Asymmetric hydrogen transfer reaction, and there are two the cis- carbocyclic ring pyrimidine nucleosides 2 of chiral centre, then hydroxyl is at methylsulfonyl ester, then it with sodium azide or acetylthio nak response, or directly reacts to obtain trans- carbocyclic ring pyrimidine nucleoside 3 with DAST.The method of the present invention obtains chiral trans carbocyclic ring pyridimine nucleosides compound, and reaction stereoselectivity is good, and yield is medium to good, and cis-selectivity and enantioselectivity are high, enriches pyrimidine nucleoside analog derivative.
Description
Technical field
Present invention relates particularly to a kind of methods of the trans- carbocyclic ring pyrimidine nucleoside of synthesis of chiral, and it is not right in organic chemistry to belong to
Claim synthesis field.
Background technique
Chiral pyridimine nucleosides compound has extensive bioactivity, such as chiral pyrimidine nucleoside Zidovudine
(Zidovudine), zalcitabine (Zalcitabine) and stavudine (Stavudine) can be used for treating HIV, chiral pyrimidine
Treatment of the nucleosides Lamivudine (Lamivudine) for hepatitis b virus infected caused disease in the liver and gallbladder；Chiral pyrimidine nucleoside
His shore (decitabine) of west, FdUrd (floxuridine), capecitabine (capecitabine), arabinose
Cytidine (cytarabine) and gemcitabine (gemcitabine) etc. are developed as new because having significant anti-tumor activity
Medicine.On the other hand, chiral carbocyclic ring nucleosides not only shows important antiviral, anti-tumor activity, and to phosphorylase and water
Solving enzyme has higher metabolic stability.Therefore it synthesizes, prepare optically pure chiral carbocyclic ring pyridimine nucleosides compound with weight
Want meaning.
Constructing chiral carbocyclic ring pyrimidine nucleoside, usually there are two types of approach.The first approach is first to design one to obtain through multistep reaction
That arrives has spatial configuration and containing different functional groups chiral carbocyclic ring, is then connect with pyrimidine bases by the method for chemistry
Get up, to form chiral carbocyclic ring nucleosides, the method for introducing chiral carbocyclic ring mainly has nucleophilic substitution, epoxide to open
Four kinds of methods such as the coupling reaction of allyl of ring reaction, Mitsunobu reaction and palladium chtalyst.Second of approach is in above-mentioned institute
An amino is introduced on the chirality five-membered ring said, pyrimidine bases is constructed from amino, thus synthesis of chiral homocyclic nucleus glycoside
Close object.But two kinds of approach are required to the chiral source of equivalent, by multistep reaction, could five yuan of carbocyclic nucleosides of synthesis of chiral, at
This is higher.
Comparatively, low cost is selected, achiral starting material cheap and easy to get is by simply more comprising asymmetric syntheses
The step reaction trans- carbocyclic ring pyrimidine nucleoside of synthesis of chiral, has very important realistic meaning.
Summary of the invention
In order to overcome drawbacks described above, the cyclic ketones 1 that the present invention uses α-pyrimidine to replace is raw material, in the work of metal Ru catalyst
Pass through the trans- carbocyclic ring pyridimine nucleosides compound of multistep reaction synthesis of chiral with lower.This method is the trans- carbocyclic ring pyrimidine of synthesis of chiral
Nucleoside compound provides a kind of easy, cheap, efficient approach.
In the present invention, a kind of method of the trans- carbocyclic ring pyrimidine nucleoside of synthesis of chiral, reaction equation is as follows:
It is characterized by comprising the following steps: being raw material with α-pyrimidine cyclic ketones 1, in chiral ruthenium catalyst, formic acid and three second
In the presence of amine, reaction obtains cis- carbocyclic ring pyrimidine nucleoside 2 in organic solvent；Then 2 react to obtain trans- carbocyclic ring with nucleopilic reagent
Pyrimidine nucleoside 3；
Wherein, n=1,2,3；R1For H or C1-C4 alkyl；PG is H or benzoyl or substituted benzoyl；X is N3, F or
AcS。
Further, in the above-mentioned technical solutions, R1Selected from hydrogen, methyl or ethyl；PG is selected from: benzoyl or to chlorobenzene
Formoxyl.
Further, in the above-mentioned technical solutions, the chiral ruthenium catalyst is selected from one kind of following catalyst:
Wherein, preferably chiral ruthenium catalyst is (R, R)-D, obtains optimum response effect.
Further, in the above-mentioned technical solutions, first step reaction dissolvent is selected from dioxane, methylene chloride, chloroform, first
Alcohol, ethyl acetate, tetrahydrofuran or acetonitrile.It is preferred that reaction dissolvent is dioxane, methylene chloride, chloroform or ethyl acetate.
Further, in the above-mentioned technical solutions, in the first step, the α-pyrimidine substitution cyclic ketones 1, formic acid, triethylamine
It is 1-2:3-10:3-10:0.005-0.02 with chiral ruthenium catalyst molar ratio.
Further, in the above-mentioned technical solutions, in second step, X=N3When, compound 2 is reacted into methylsufonyl chloride
Ester then obtains product 3 with reaction of sodium azide；When X=AcS, compound 2 reacts into ester with methylsufonyl chloride, then with
AcSK reacts to obtain product 3；When X=F, compound 2 directly reacts to obtain product 3 with DAST.
Further, in the above-mentioned technical solutions, in second step, X=N3Or when AcS, cis- carbocyclic ring pyrimidine nucleoside 2, first
Base sulfonic acid chloride and sodium azide or AcSK molar ratio are 1:1-3:1-5；When X=F, cis- carbocyclic ring pyrimidine nucleoside 2 with DAST moles
Than for 1:2-3.
Further, in the above-mentioned technical solutions, first step reaction temperature is 0-30 DEG C, and second step reaction temperature is -40
DEG C to 80 DEG C.
Invention the utility model has the advantages that
The present invention provides a kind of easy, cheap, efficient synthetic method for the trans- carbocyclic ring pyrimidine nucleoside of synthesis of chiral, instead
Raw material is answered to be easy to get, chiral trans carbocyclic ring pyridimine nucleosides compound can be obtained in product structure diversification, two steps.Wherein, first
Reaction yield is good to outstanding in step, and along anti-cis-selectivity > 20/1dr, enantioselectivity is up to 99%ee, be second step with
Trans product is generated after nucleopilic reagent reaction provides fabulous chirality basis.
Figure of description
Fig. 1 is compound 4a single crystal X diffraction spectrogram in embodiment 5.
Specific embodiment
Embodiment 1
First step condition optimizing
[a] unless stated otherwise, the step of reaction, is as follows: 1a (0.1mmol), 0.5-2% catalyst, 1mL solvent,
HCO270 μ L of H/TEA (1:1), 1 day [b] > 20:1dr of middle reaction at 27 DEG C, dr value are received by nuclear-magnetism detection crude product [c] separation
Rate [d] ee value analyzes [e] HCO by chiral column2H/TEA=2.5:1 [f] HCO2H/TEA=0.2:1.
In the screening process of reaction condition, influence (label 1-4) of the metallic catalyst to reaction has been primarily looked at.Simultaneously
Pass through influence of the control different ligands to reaction and consider price factor, has finally been determined that catalyst D is optimum catalyst.It
After have selected optimum solvent dioxane, HCO2H/TEA=1:1.
The investigation of reaction condition: (by taking label 13 as an example)
In 10mL reaction flask, the cyclopentanone 1a (31.2mg, 0.1mmol) of α-(5- methyl) urea pyrimidine substitution is added, urges
Agent D (0.7mg, 1mol%) and 1mL Isosorbide-5-Nitrae-dioxane, are subsequently added into HCO270 μ L of H/TEA=1:1 mixed solvent.It will be anti-
Should pipe be placed in 27 DEG C react 24 hours.It is tracked and is reacted with TLC, after terminating reaction, be concentrated in vacuo organic phase, then obtained through column chromatography
White solid 2a, yield 92%, 96%ee, dr > 20:1, m.p.86.1-90.7 DEG C.[α]D 20=-73.98 (c=0.246,
CH2Cl2)；HPLC CHIRALCEL OD-H, n-hexane/2-propanol=80/20, flow rate=0.8mL/min, λ
=250nm, retention time:20.420min, 24.577min；1H NMR(600MHz,CDCl3): 7.93 (d, J=
7.8Hz, 2H), 7.63 (t, J=7.2Hz, 1H), 7.50-7.44 (m, 3H), 4.68 (d, J=11.4Hz, 1H), 4.32 (s,
1H),2.20-2.17(m,1H),2.07-1.94(m,6H),1.74-1.63(m,2H)；13C NMR(150MHz,CDCl3):
169.5,163.1,150.8,139.4,135.1,131.8,130.6,129.3,109.3,71.8,59.3,33.3,26.5,
20.2,12.8；HRMS(ESI-TOF):exact mass calcd for C17H19N2O4(M+H)+requires m/z
315.1339,found m/z 315.1330.
Embodiment 2
In 10mL reaction flask, cyclopentanone 1b (29.8mg, 0.1mmol), the catalyst that α-(5-H) urea pyrimidine replaces is added
D (0.7mg, 1mol%) and 1mL dioxane.It is subsequently added into HCO270 μ L of H/TEA=1:1 mixed solvent, reaction tube is placed in
27 DEG C are reacted 24 hours.It is tracked and is reacted with TLC, after terminating reaction, be concentrated in vacuo organic phase, then obtain colourless liquid through column chromatography
Body 2b, yield 96%, 97%ee, dr > 20:1, [α]D 20=-49.40 (c=0.250, CH2Cl2)；HPLC CHIRALCEL OD-
H, n-hexane/2-propanol=80/20, flow rate=0.8mL/min, λ=250nm, retention time:
24.179min,36.556min；1H NMR(400MHz,CDCl3):7.97-7.84(m,2H),7.67-7.61(m,2H),7.52-
7.48 (m, 2H), 5.76 (d, J=8.4Hz, 1H), 4.74-4.68 (m, 1H), 4.34-4.31 (m, 1H), 2.04-1.97 (m,
4H),1.77-1.63(m,2H)；13C NMR(150MHz,CDCl3):169.3,162.5,150.7,143.5,135.2,131.6,
130.7,129.3,100.8,71.6,59.4,33.3,26.6,20.2；HRMS(ESI-TOF):exact mass calcd for
C16H17N2O4(M+H)+requires m/z 301.1183,found m/z 301.1174.
Embodiment 3
In 10mL vacuum tube, the cyclopentanone 1c (32.6mg, 0.1mmol) of α-(5- ethyl) urea pyrimidine substitution is added, urges
Agent D (0.7mg, 1mol%) and 1mL dioxane, are added followed by HCO270 μ L of H/TEA=1:1 mixed solvent.It will reaction
Pipe is placed in 27 DEG C and reacts 24 hours.It is tracked and is reacted with TLC, after terminating reaction, be concentrated in vacuo organic phase, then chromatograph and obtain through column
White solid 2c yield 93%, 95%ee, dr > 20:1, m.p.154.3-156.3 DEG C of [α]D 20=-38.33 (c=0.420,
CH2Cl2)；HPLC CHIRALCEL AS-H, n-hexane/2-propanol=70/30, flow rate=0.8mL/min, λ
=256nm, retention time:7.970min, 12.263min；1H NMR(600MHz,CDCl3)δ7.94-7.92(m,
2H),7.64-7.61(m,1H),7.49-7.47(m,2H),7.40-7.39(m,1H),4.70-4.66(m,1H),4.32-4.29
(m,1H),2.39-2.35(m,2H),2.09-2.04(m,1H),2.02-1.95(m,3H),1.74-1.62(m,2H),1.14
(t, J=7.2Hz, 3H)；13C NMR(150MHz,CDCl3)δ169.6,162.7,150.7,138.7,135.1,131.8,
130.6,129.2,114.9,71.8,59.4,33.3,26.5,20.3,20.2,12.9；HRMS(ESI-TOF):exact mass
calcd for C18H21N2O4(M+H)+requires m/z329.1496,found m/z 329.1487.
Embodiment 4
According to the reaction condition in embodiment 2-3, only reaction substrate is changed, obtains following reaction result:
Embodiment 5
In 50mL round-bottomed flask, Carbocyclic nucleoside analogues 2a (157.1mg, 0.5mmol) and 10mL dichloromethane is added
Reaction is cooled to 0 DEG C by alkane, and triethylamine (173 μ l, 1.25mmol) is added and mesyl chloride (58 μ L, 0.75mmol) reacts afterwards
3-4 hours.It is detected with TLC, after reacting completely, is concentrated in vacuo reaction solution, then chromatographs (CH through column2Cl2/ MeOH=80:1)
It obtains white solid 4a (single crystal X diffraction spectrogram is Fig. 1), yield 94%, 95%ee, m.p.140.4-142.5 DEG C.[α]D 20=-
57.58 (c=0.264, CH2Cl2)；HPLC CHIRALCEL IA, n-hexane/2-propanol=15/85, flow rate
=0.3mL/min, λ=250nm, retention time:18.571min, 19.698min；1H NMR(600MHz,CDCl3)δ
7.94 (d, J=7.8Hz, 2H), 7.57 (t, J=7.8Hz, 1H), 7.42 (t, J=7.8Hz, 2H), 7.20 (s, 1H), 5.11
(t, J=4.8Hz, 1H), 4.71-4.67 (m, 1H), 2.89 (s, 3H), 2.15-1.97 (m, 5H), 1.91 (s, 3H), 1.72-
1.66(m,1H)；13C NMR(150MHz,CDCl3)δ169.3,162.8,150.6,137.2,135.2131.5,130.9,
129.2,110.3,81.5,58.6,38.2,30.7,25.6,19.9,12.8；HRMS(ESI-TOF):exact mass calcd
for C18H21N2O6S(M+H)+requires m/z 393.1115,found m/z393.1108.
In 25mL round-bottomed flask, Carbocyclic nucleoside analogues 4a (117.6mg, 0.3mmol), DMF (3mL) and NaN is added3
Reaction is heated to 50 DEG C, reacted 24 hours by (97.5mg, 1.5mmol).It is detected with TLC, after reacting completely, 10mL is added
Distilled water is extracted in three times with 30mL ethyl acetate, is concentrated in vacuo organic phase, is then obtained through column chromatography (PE/EA=2:1)
Yellow solid 3a, yield 76%, 93%ee, m.p.158.4-165.3 DEG C.[α]D 20=10.92 (c=0.200, CH2Cl2)；
HPLC CHIRALCEL ID, n-hexane/2-propanol=70/30, flow rate=0.8mL/min, λ=256nm,
retention time:24.443min,26.077min；1H NMR(400MHz,CDCl3):8.53(s,1H),6.94-6.93
(m, 1H), 4.35 (q, J=7.6Hz, 1H), 4.14 (q, J=7.6Hz, 1H), 2.24-2.11 (m, 2H), 1.99-1.89 (m,
5H),1.88-1.72(m,2H)；13C NMR(100MHz,CDCl3):163.5,150.7,138.3,111.5,64.9,64.5,
29.9,28.1,21.3,12.7；HRMS(ESI-TOF):exact mass calcd for C10H14N5O2(M+H)+requires
m/z236.1142,foundm/z 236.1151.
Embodiment 6
In 25mL round-bottomed flask, Carbocyclic nucleoside analogues 2a (31.4mg, 0.1mmol), DCM (1mL) and diethyl is added
Amido sulfur trifluoride (DAST) (26.7 μ L, 0.2mmol)), reaction temperature is down to -40 DEG C, is reacted 10 minutes.It is detected with TLC,
After reacting completely, vacuum revolving removes solvent, then obtains colourless liquid 5a, yield through column chromatography (PE/EA=2:1)
51%, 93%ee；[α]D 20=9.02 (c=0.508, CH2Cl2)；HPLC CHIRALCEL ID,n-hexane/2-propanol
=70/30, flow rate=0.8mL/min, λ=256nm, retention time:21.400min, 22.387min；1H
NMR(600MHz,CDCl3): 7.93-7.91 (m, 2H), 7.65 (t, J=7.2Hz, 1H), 7.50 (t, J=7.8Hz, 2H),
7.07(s,1H),5.40-5.29(m,1H),4.43-4.35(m,1H),2.22-2.08(m,2H),2.00-1.97(m,5H),
1.91-1.80(m,2H)；13C NMR(150MHz,CDCl3):169.0,162.9,149.6,139.7,135.3,131.6,
(130.6,129.3,111.2,97.5 J=179.7Hz), 68.8 (J=25.5Hz), 31.9 (J=22.5Hz), 29.2 (J=
4.5Hz),22.4,12.6；HRMS(ESI-TOF):exact mass calcd for C17H18FN2O3(M+H)+requires
m/z 317.1296,foundm/z 317.1291.
Embodiment 7
In 25mL round-bottomed flask, be added Carbocyclic nucleoside analogues 4a (39.2mg, 0.1mmol), DMF (1mL), three (3,
6- dioxaheptyl) amine (TDA) (96.0 μ L, 0.3mmol) and AcSK (22.8mg, 0.2mmol), reaction is heated to 80 DEG C,
Reaction 24 hours.It is detected with TLC, after reacting completely, 5mL distilled water is added and is extracted in three times with 15mL ethyl acetate, very
Sky concentration organic phase, then obtains yellow liquid 6a, yield 57%, 93%ee through column chromatography (PE/EA=4:1)；[α]D 20=-
17.34 (c=0.372, CH2Cl2)；1H NMR(400MHz,CDCl3):7-99-7.96(m,2H),7.65-7.61(m,1H),
7.50-7.46 (m, 2H), 7.11-7.10 (m, 1H), 4.71 (s, 1H), 3.95 (q, J=9.2Hz, 1H), 2.31 (s, 3H),
2.28-2.14 (m, 2H), 1.98 (d, J=1.2Hz, 3H), 1.95-1.82 (m, 3H), 1.73-1.65 (m, 1H)；13C NMR
(100MHz,CDCl3):195.8,169.3,162.9,150.2,137.2,135.0,131.8,130.7,129.2,111.3,
45.6,31.1,30.7,29.9,22.8,12.8；HRMS(ESI-TOF):exact mass calcd for C19H21N2O4S(M+
H)+requires m/z 373.1217,found m/z 373.1209.
Embodiment above describes basic principles and main features of the invention and advantages.The technical staff of the industry should
Understand, the present invention is not limited to the above embodiments, and the above embodiments and description only describe originals of the invention
Reason, under the range for not departing from the principle of the invention, various changes and improvements may be made to the invention, these changes and improvements are each fallen within
In the scope of protection of the invention.
Claims (10)
1. a kind of method of the trans- carbocyclic ring pyrimidine nucleoside of synthesis of chiral, reaction equation are as follows:
It is characterized by comprising the following steps: being raw material with α-pyrimidine cyclic ketones 1, deposited in chiral ruthenium catalyst, formic acid and triethylamine
Under, reaction obtains cis- carbocyclic ring pyrimidine nucleoside 2 in organic solvent；Then 2 react to obtain trans- carbocyclic ring pyrimidine with nucleopilic reagent
Nucleosides 3；Wherein, n=1,2,3；R1For H or C1-C4 alkyl；PG is H or benzoyl or substituted benzoyl, X N3, F or
AcS。
2. the method for the trans- carbocyclic ring pyrimidine nucleoside of synthesis of chiral described according to claim 1, it is characterised in that: R1Selected from hydrogen, first
Base or ethyl；PG is selected from benzoyl or to chlorobenzene formacyl.
3. the method for the trans- carbocyclic ring pyrimidine nucleoside of synthesis of chiral described according to claim 1, it is characterised in that: the chirality is urged
Agent is selected from one kind of following catalyst:
4. the method for the trans- carbocyclic ring pyrimidine nucleoside of the synthesis of chiral according to claim 3, it is characterised in that: the chirality ruthenium
Catalyst is selected from (R, R)-D.
5. the method for the trans- carbocyclic ring pyrimidine nucleoside of synthesis of chiral described according to claim 1, it is characterised in that: first step reaction
Solvent is selected from dioxane, methylene chloride, chloroform, methanol, ethyl acetate, tetrahydrofuran or acetonitrile.
6. the method for the trans- carbocyclic ring pyrimidine nucleoside of the synthesis of chiral according to claim 5, it is characterised in that: first step reaction
Solvent is selected from dioxane, methylene chloride, chloroform or ethyl acetate.
7. the method for the trans- carbocyclic ring pyrimidine nucleoside of synthesis of chiral described according to claim 1, it is characterised in that: in the first step,
Cyclic ketones 1, formic acid, triethylamine and the chiral ruthenium catalyst molar ratio that the α-pyrimidine replaces are 1-2:3-10:3-10:0.005-
0.02。
8. the method for the trans- carbocyclic ring pyrimidine nucleoside of synthesis of chiral described according to claim 1, it is characterised in that: second step X=N3
When, compound 2 reacts into ester with methylsufonyl chloride, and product 3 is then obtained with reaction of sodium azide；When X=AcS, compound 2 with
Methylsufonyl chloride is reacted into ester, then reacts to obtain product 3 with AcSK；When X=F, compound 2 is directly reacted with DAST to be produced
Product 3.
9. the method for the trans- carbocyclic ring pyrimidine nucleoside of the synthesis of chiral according to claim 8, it is characterised in that: in second step, X
=N3Or when AcS, cis- carbocyclic ring pyrimidine nucleoside 2, methylsufonyl chloride and sodium azide or AcSK molar ratio are 1:1-3:1-5；X=
When F, cis- carbocyclic ring pyrimidine nucleoside 2 is 1:2-3 with DAST molar ratio.
10. the method for the trans- carbocyclic ring pyrimidine nucleoside of synthesis of chiral described according to claim 1, it is characterised in that: the first step is anti-
Answering temperature is 0-30 DEG C, and second step reaction temperature is -40 DEG C to 80 DEG C.
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