CN106336443A - Synthesis method of nucleoside compound - Google Patents
Synthesis method of nucleoside compound Download PDFInfo
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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Abstract
The invention relates to a synthesis method of a nucleoside compound, in particular to a preparation method of a compound shown as formula I and a compound shown as formula II in the specification. In the formula I and formula II, R1 and R2 are respectively a hydroxyl protecting group independently, preferably benzoyl, triphenylmethyl, disubstituted phenyl, acetyl or tert-butyldimethylsilyl; R3 and R4 are alkyl (preferably alkyl of C1-C10, more preferably methyl and ethyl) or halogen (like F, Cl or Br); and B is any of the following groups shown as the specification, wherein R5 is hydrogen or alkyl (preferably alkyl of C1-C10, more preferably methyl); X is hydroxyl or amino; and Y is sulfur or selenium.
Description
Technical field
The present invention relates to pharmaceutical synthesis field, specifically, it is related to the synthetic method of a class nucleoside compound.
Background technology
Gemcitabine Hydrochloride (gemcitabine hydrochloride), chemical entitled gemcitabine hydrochloride (β-
Isomer), shown in following structure 1, it is the homologue of nucleoside, belong to cell cycle specific antineoplastic agent.Gemcitabine is one
Plant effective anticancer (" antitumor " or " cytotoxicity ") medicine, classify as antimetabolite, be a line antitumor drug.1996
Year, U.S. fda have approved the Gemcitabine Hydrochloride (trade name that Li Lai company (eli lilly and company) researches and develops
Gemzar) as the first-line drug for the treatment of cancer of pancreas, ratify this medicine within 1998 again and be used for treating nonsmall-cell lung cancer.2009
Global marketing share at 1,700,000,000 dollars, and its patent is expired in 2010.Gemcitabine can restrain cancerous cell with selectivity
Dna and rna synthesizes, thus leading to cancer cell death.It can be used for anti-pancreatic cancer, pulmonary carcinoma, nonsmall-cell lung cancer, bladder
Cancer, soft tissue sarcoma, metastatic breast cancer and ovarian cancer, and potential for resisting other tumors.
This medicine is applied to treatment inoperable late period or transitivity cancer of pancreas and treatment Local advancement or transitivity non-small cell
Pulmonary carcinoma, additionally, this medicine can be also used for treat Advanced non-small cell lung cancer, and cancer of pancreas, bladder cancer, breast carcinoma and
Other entity tumors (Guo Dongmei, Li Chong etc., " gemcitabine clinic quotes progress ", " Chinese Chinese medicine modern distance education "
Volume 9 the 13rd phase, in July, 2011).Gemcitabine Hydrochloride mechanism of action is unique, mainly acts on the tumor that dna synthesizes the phase
Cell, have the features such as antitumor spectra is wide and other chemotherapeutics no crossing drug resistant, and toxic reaction is no superimposed (van moorsel, c.j.a.,
g.j.peters,and h.m.pinedo,gemcitabine:future prospects of single-agent and combination
studies.the oncologist,1997.2(3):p.127-134；cerqueira,n.m.f.s.a.,p.a.fernandes,and m.j.
ramos,understanding ribonucleotide reductase inactivation by gemcitabine.chemistry–a
european journal,2007.13(30):p.8507-8515).It is that only one is ratified treatment late period by fda so far
The first-line drug of cancer of pancreas.
But, gemcitabine (Gemcitabine Hydrochloride) does not have the form of pill, using inconvenience, can only be by vein large bolus injection (
Secondary can up to hundreds of to 1,000 milligrams), once in a week, up to the several months.Although gemcitabine energy effective antitumor, due to using agent
Amount is high, causes many toxic and side effects.(the use patient more than 30%) in common adverse effect: influenza-like symptom (muscle there is
Pain, heating, headache, fear of cold, weak), have a fever (initial dose in 6-12 hour), fatigue, nauseous (slight),
Vomiting, appetite is poor, erythra, low numeration of leukocyte (increasing the risk of infection), and low platelet counts (increase bleeding risk), low red
Cell counting (anemia, tired, weak, shortness of breath), other position swelling of arm, lower limb or body, this medicine is also possible to
There is harmful effect to the function of liver and kidney.
As the first-line drug uniquely treating advanced pancreatic cancer so far, its existing preparation method still suffers from three-dimensional choosing to gemcitabine
The problems such as selecting property is high, its high consumption and drug toxicity reaction equally allow people worry simultaneously.Currently develop new Ji further
His shore analog (for example monatomic seleno compound) of west, as the high-quality alternative medicine of gemcitabine antitumor drug.
Selenium nucleoside can be used for antitumor drug innovation research, conversion and exploitation, to produce novel biochemical antitumor drug.Nucleoside
It is successfully used for treating cancer with nucleotide analog and nucleoside base as antitumor agent.
Content of the invention
The present invention relates to the preparation method of the new nucleoside compound of a class.The structure of described nucleoside compound is as follows:
Wherein, r1And r2It is separately hydroxyl protecting group, preferably benzoyl, trityl, di-substituted-phenyl, second
Acyl group or t-butyldimethylsilyi；r3And r4It is alkyl (preferably c1-c10Alkyl, more preferably methyl, ethyl) or
Halogen (as f, cl or br)；
B is following any group:
Wherein, r5It is hydrogen or alkyl (preferably c1-c10Alkyl, more preferably methyl)；X is hydroxyl or amino；Y be sulfur or
Selenium；
Wherein, when x is for oh, there is above-mentioned tautomer in it.
Wherein, formula i compound is as the intermediate in formula ii compound.
The preparation method of above-mentioned formula ii compound comprises the steps:
1). compound shown in formula iii is reacted with formula iv or formula vi compound, respectively obtains formula v or formula vii compound；
Wherein,
r1And r2Hydroxyl protecting group independently of one another, preferably benzoyl, trityl, di-substituted-phenyl, acetyl group or
T-butyldimethylsilyi；
r3And r4It is alkyl (preferably c1-c10Alkyl, more preferably methyl, ethyl) or halogen (as f, cl or br)；
r5It is hydrogen or alkyl (preferably c1-c10Alkyl, more preferably methyl)；
X is hydroxyl or amino；Y is sulfur or selenium；
2). step 1) formula v that obtains or formula vii compound be through deprotection base r1, r2After obtain formula ii compound.
Wherein, above-mentioned steps 1) in, when the x of formula iv compound is oh, there are following tautomeric forms:
In a preferred embodiment, the step 1 of above-mentioned reaction) be:
A., in the solution (preferably acetonitrile solution) of compound iv or vi, (i.e. n, o- are double (dimethyl silicon substrate) to add bsa
Acetamide) reaction after；
B. removing reaction dissolvent, addition toluene, compound iii and tmsotf (that is, TMS triflate),
React at 80 DEG C to 110 DEG C (and lower or higher temperature) and midbody compound v or vii is obtained.
Above-mentioned steps b are preferably carried out under argon protection.
In a preferred embodiment, the step 2 of above-mentioned reaction) be:
By midbody compound v, vii is dissolved in react in alkali alcosol (as 7n methanolic ammonia solution) and formula ii compound is obtained.
In one embodiment of the invention, the preparation method of formula iii compound is as follows:
By compound 2 with bromide reagent (if described bromide reagent is the acetum of 33%hbr) in nonpolar or low pole
In solvent (such as dichloromethane, chloroform or toluene), reaction is obtained compound iii；
Wherein, r1And r2It is hydroxyl protecting group independently of one another, preferably benzoyl, trityl, di-substituted-phenyl, second
Acyl group or t-butyldimethylsilyi；r3And r4It is alkyl (preferably c1-c10Alkyl, more preferably methyl, ethyl) or
Halogen (as f, cl or br)；Lg is mesyloxy (oms), the leaving group such as acetoxyl group (oac).
In one embodiment of the invention, the preparation method of formula iv compound is as follows:
By in alcohol (such as ethanol, the n-butyl alcohol) solution of compound 3a (or 3b) and thiourea (4), in strong organic base (such as
Feldalat NM, Sodium ethylate, n-butyl alcohol sodium, sodium tert-butoxide, potassium tert-butoxide) in the presence of, reaction obtains compound iva, ivb
Or ivc.
In another embodiment of the present invention, the preparation method of formula iv compound is as follows:
2- chlorine cytosine (compound 5), in the presence of sodium hydrogen selenide, prepares compound ivd.
Step 1 of the present invention) in, for the reaction of the pyrimidine base analogue shown in formula iv and formula iii compound, need formula iv
2 sulfur of compound, the keto-acid of selenium are converted into corresponding enol form to make described base and formula iii compound correctly be condensed,
Wherein Enolization is to be protected by the enol of 2 by forming silicon ether.Conventional silicon substrate protects reagent: hexamethyl two silicon
Amine, trim,ethylchlorosilane, or n, double (dimethyl silicon substrate) acetamide of o-, wherein preferably n, double (dimethyl silicon substrate) second of o-
Amide；The reaction temperature of this reaction is 80～110 DEG C (and lower or higher temperature).Catalysts are tmsotf.
Reaction dissolvent is low polar solvent, including toluene, carbon tetrachloride, or 1,2- dichloroethanes etc., and wherein preferred toluene.
Step 1 of the present invention) in, for the reaction of the purine type bio-logical bases shown in formula vi and formula iii compound, then generally adopt
Different condensation strategies, because this base analogue has more reaction centers, one of the most frequently used strategy is related to a kind of highly basic (such as
Feldalat NM, Sodium ethylate, n-butyl alcohol sodium, sodium tert-butoxide, potassium tert-butoxide etc.) seize hydrogen from n-7 position or n-9 position, thus producing
Higher active anion, more effectively attacks the 1- position of formula iii compound；This reaction dissolvent is polar solvent, preferably two
Methylformamide, dimethyl acetylamide or the tert-butyl alcohol, reaction temperature is 40-140 DEG C.
The step 2 of the present invention) in, work as r1And r2Be respectively dehydrogenation outside group when, reaction under the conditions of strong or weak alkali hydrolyze
Remove r1And r2The polar solvent (as methanol, ethanol, n-butyl alcohol, the tert-butyl alcohol) of group, preferably ammonia or potassium carbonate.
Specific embodiment
The embodiment of following offers is to further illustrate the present invention, but this does not imply that any limitation of the invention.
Embodiment 1
The preparation of fluoro- d- erythro form-five furanose -3,5- dibenzoate of compound α -1- bromo- 2- deoxidation -2,2- two
According to document (howell, et.al., journal of organic chemistry 1988, v.p.85-88) method, by commercially purchasing
Fluoro- d- erythro form-five furanose -3,5- benzhydryl ester -1- methanesulfonates of compound 2- deoxidation -2,2- two obtaining is converted into compound α -1- bromine
Fluoro- d- erythro form-five furanose -3,5- dibenzoate of -2- deoxidation -2,2- two.Specific preparation method is as follows:
By sugar initial for 22.8g (50mmol), i.e. 2- deoxidation -2, fluoro- d- erythro form-five furanose -3 of 2- bis-, 5- benzhydryl ester -1- first sulphur
Acid esters, is dissolved in 100ml chloroform, adds content 33% hydrogen bromide acetic acid solution of 36g (3.0eq), reaction system at room temperature
It is stirred at room temperature 6 days.After reaction terminates, add 150ml water washing every time, altogether twice.Then use 150ml saturation every time
Sodium bicarbonate aqueous solution washs, altogether twice.Organic faciess anhydrous magnesium sulfate is dried, and decompression precipitation obtains flaxen grease.Slightly
Product are dissolved in the petroleum ether of 200ml heat, and cold filtration removes insoluble matter, filtrate decompression precipitation, and the grease obtaining heats again
It is dissolved in 150ml petroleum ether, cold filtration obtains 13.5g fine acicular product.Mother solution decompression precipitation, Repeat-heating is dissolved on a small quantity
Petroleum ether, cold filtration obtains 1.7g product.(eluent is by 100% petroleum ether to 5% acetic acid second through silica gel post separation for mother solution
Ester petroleum ether), 17.6g product, yield 80% are obtained.
Embodiment 2
The preparation of 2- selenium cytosine
By 2- chlorine cytosine (2g, 15.4mmol) add argon protection sodium hydrogen selenide ethanol solution (preparation process: by selenium (3g,
React 30 minutes at 38.0mmol) adding 10 DEG C in dehydrated alcohol (100ml) with sodium borohydride (1.75g, 46.2mmol)),
It is heated to reflux 48 hours, cooling, add 10ml water, sucking filtration, filter cake is suspended in 15ml dehydrated alcohol, adds 220mg
Sodium borohydride, stirring reaction 30 minutes, sucking filtration, it is dried, obtain off-white powder (1.1g), yield 39%.
Analytical data is:1H-nmr (dmso-d6) δ: 12.39 (s, 1h), 7.69and 7.84 (ss, 2h), 7.40 (d, j=6.0hz,
1h), 6.07 (d, j=6.0hz, 1h)；13c-nmr(dmso-d6)δ:175.7,161.6,142.6,97.6；hrms
(esi-tof), c4h5n3se, [m+na]=197.9538 (calc.197.9546).
Embodiment 3
The preparation of 2- sulfur cytosine
Under nitrogen protection, at 40～50 DEG C, add metallic sodium (4.8g) in n-butyl alcohol (88ml), stirring is molten clear, so
Add thiourea (16g) and 3,3- diethoxy propionitrile (28g) in backward reactant liquor, be heated to reflux 5 hours, be cooled to room temperature,
Adjust ph to 7～8 with acetic acid, be filtrated to get yellow solid, be recrystallized to give flaxen 2- sulfur cytosine (12g) with water, receive
Rate 48%.
Analytical data:1H-nmr (600mhz, dmso-d6) δ: 11.94 (s, 1h), 7.54 (s, 2h), 7.39 (s, 1h), 5.91 (s,
1h).
Embodiment 4
The preparation of 6- selenium guanine (via)
Add compound (6), anhydrous n, n- diformamide, dichloroethanes in reaction bulb, be cooled to 0 DEG C, be slowly added dropwise three
Chlorethoxyfos, insulation reaction 1 hour after completion of dropwise addition, then temperature rising reflux react 7 hours.Reactant liquor is poured slowly in frozen water, stirs
Mix 30 minutes, divide and go organic faciess.Aqueous phase adjusts ph to 7～8 with 10% sodium hydrate aqueous solution, has substantial amounts of solid to separate out, mistake
Filter.Filter cake is dissolved in 12% aqueous acetic acid, is heated to 70 DEG C, stirs 1 hour, is cooled to room temperature, filters.Filter cake is molten
In 10% sodium hydrate aqueous solution, it is stirred at room temperature 3 hours, then adjust ph to 7.5 with the hydrochloric acid of 6mol/l.Filter, filter
Cake is washed, is dried.Obtain flaxen compound (7).
6- chlorine guanine (7) is added the sodium hydrogen selenide ethanol solution (preparation process: be added to the selenium prepared in advance of argon protection
In hydrogenation sodium ethoxide solution (preparation process: selenium and sodium borohydride are reacted 30 minutes in less than 20 DEG C in dehydrated alcohol), plus
Hot reflux 48 hours, cooling, add a small amount of water, sucking filtration, filter cake is suspended in dehydrated alcohol, adds 0.5eq sodium borohydride,
Stirring reaction 30 minutes, sucking filtration, it is dried, obtain target compound via.
Embodiment 5
The preparation of β -1- (2 '-deoxidation -2 ', 2 '-two fluoro- 3 ', 5 '-dibenzoyl-β-d- erythro form-furanoses) -2- sulfur cytosine
2- sulfur cytosine (0.2g) is suspended in 10ml acetonitrile, adds bsa (1.6g), reactant mixture stirring 1 under room temperature
Hour forms the solution of clarification.After removing solvent under reduced pressure, under argon protection, sequentially add toluene (10ml), bromine sugar (0.6g) and
tmsotf(1.2g).Under the protection of 80 DEG C of argon, insulation reaction is overnight.Reaction is processed through acid-alkali washing, column chromatography purification
(ch2cl2/meoh, 98/2, v/v) obtain sterling 1- (2 '-deoxidation -2 ', 2 '-two fluoro- 3 ', 5 '-dibenzoyl-β-d- erythro form-furan
Sugar) -2- sulfur cytosine (0.38g), yield 34.4%.
Analytical data:1h-nmr(cdcl3) δ: 8.13-8.15 (m, 2h), 8.10 (d, j=5.8hz, 1h), 8.07 8.09 (m,
2h), 7.43 7.66 (m, 6h), 6.89 (m, j=2.4hz, 1h), 6.23 (d, j=5.8hz, 1h), 5.69 (dd, j=4.8,13.8
Hz, 1h), 5.03 (brs, 2h), 4.66 4.74 (m, 3h) .13c nmr (cdcl3) δ: 167.09,165.63,164.46,
162.12,155.67,133.48,132.82,129.66,129.32,128.90,128.18,127.95,127.79,124.28,123.47,
122.59,122.51,120.82,101.61,86.00,85.85,85.77,85.61,79.49,72.30,72.18,72.06,71.94,62.50；
Hrms (esi-tof), c23h19f2n3o5s, [m+h] +=488.1098 (calc.488.1092).
Embodiment 6
The preparation of 1- (2 '-deoxidation -2 ', 2 '-two fluoro- 3 ', 5 '-dibenzoyl-β-d- erythro form-furanoses) -2- selenium cytosine
2- selenium cytosine (1.0g) is suspended in 15ml acetonitrile, adds bsa (1.98g), reactant mixture stirring 1 under room temperature
Hour forms the solution of clarification.After removing solvent under reduced pressure, under argon protection, sequentially add toluene (35ml), bromine sugar (1.4g) and
tmsotf(1.4g).Under the protection of 80 DEG C of argon, insulation reaction is overnight.Reaction is processed through acid-alkali washing, column chromatography purification
(ch2cl2/ meoh, 98/2, v/v) obtain sterling 1- (2 '-deoxidation -2 ', 2 '-two fluoro- 3 ', 5 '-dibenzoyl-β-d- erythro form-furan
Sugar) -2- selenium cytosine (1.2g), yield 60%.
Analytical data: 1h-nmr (cdcl3) δ: 8.15-8.08 (m, 2h), 8.08-8.03 (m, 2h), 8.00 (d, j=5.9hz,
1h), 7.67-7.59 (m, 1h), 7.59-7.53 (m, 1h), 7.53-7.46 (m, 2h), 7.46-7.37 (m, 2h), 7.05 (dd, j=
12.9,2.9hz, 1h), 6.29 (d, j=5.9hz, 1h), 5.71-5.61 (m, 1h), 5.37 (s, 2h), 4.77-4.61 (m, 3h).
13c-nmr(cdcl3)δ:165.53,164.57,164.55,164.25,163.17,153.98,133.26,132.60,129.09,
128.79,127.95,127.69,125.02,123.33,123.27,121.58,101.67,84.94,84.77,84.73,84.55,79.64,
72.29,72.17,72.05,71.93,62.14；Hrms (esi-tof), c23h19f2n3o5se, [m+h] +=536.0539
(calc.536.0536).
Embodiment 7
The preparation of 1- (2 '-deoxidation -2 ', 2 '-two fluoro- 3 ', 5 '-dibenzoyl-β-d- erythro form-furanoses) -2- deracil
2- thiouracil (2.0g) is suspended in 20ml acetonitrile, adds bsa (5g), reactant mixture stirring 0.5 under room temperature
Hour forms the solution of clarification.After removing solvent under reduced pressure, under argon protection, sequentially add toluene (20ml), bromine sugar (1g) and
tmsotf(1g).Under the protection of 110 DEG C of argon, insulation reaction is overnight.Reaction is processed through acid-alkali washing, column chromatography purification
(ch2cl2/ meoh, 99/1, v/v) 1- (2 '-deoxidation -2 ', 2 '-two fluoro- 3 ', 5 '-dibenzoyl-β-d- erythro form-furanoses) -2- thiourea
Pyrimidine 0.47g, yield 42.3%.
Analytical data: 1h-nmr (cdcl3) δ: 8.13 (dd, j=8.0,1.5hz, 2h), 8.09-8.02 (m, 2h), 7.94 (d, j
=6.6hz, 1h), 7.70-7.62 (m, 1h), 7.62-7.55 (m, 1h), 7.52 (t, j=7.7hz, 2h), 7.44 (t, j=7.7hz,
2h), 6.94 (dd, j=11.7,3.2hz, 1h), 6.32 (d, j=6.6hz, 1h), 5.81-5.59 (m, 1h), 4.72 (dd, j=10.1,
4.0hz, 2h), 4.67 (dd, j=13.2,5.3hz, 1h) .13c-nmr (cdcl3) δ: 165.48,164.25,164.10,157.88,
154.38,133.60,132.88,129.71,129.30,128.75,128.19,127.95,127.59,124.09,122.38,122.31,
120.61,111.60,86.13,86.04,85.89,79.87,72.03,71.92,71.80,71.68,62.12；hrms(esi-tof),
C23h18f2n2o6s, [m+na]=511.0756 (calc.511.0751)
Embodiment 8
The preparation of 1- (2 '-deoxidation -2 ', 2 '-two fluoro- 3 ', 5 '-dibenzoyl-β-d- erythro form-furanoses) -2- sulfur thymus pyrimidine
2- sulfur thymus pyrimidine (2.0g) is suspended in 20ml acetonitrile, adds bsa (5g), reactant mixture stirring 0.5 under room temperature
Hour forms the solution of clarification.After removing solvent under reduced pressure, under argon protection, sequentially add toluene (20ml), bromine sugar (1g) and
tmsotf(1g).Under the protection of 110 DEG C of argon, insulation reaction is overnight.Reaction is processed through acid-alkali washing, and column chromatography purification (is washed
De- agent ch2cl2/ meoh, 99.5/0.5, v/v) 1- (2 '-deoxidation -2 ', 2 '-two fluoro- 3 ', 5 '-dibenzoyl-β-d- erythro form-furan
Sugar) -2- sulfur thymus pyrimidine (0.7g), yield 61%.
Analytical data: 1h-nmr (cdcl3) δ: 8.06-8.14 (m, 4h), 7.80 (d, j=1.2hz, 1h), 7.43-7.87 (m,
6h), 6.88 (m, j=2.4hz, 1h), 5.67 (dd, j=13.2,4.8hz, 1h), 4.67-4.76 (m, 3h), 2.06 (d, j=1.2
hz,3h).13c nmr(cdcl3)δ:165.50,164.64,164.26,154.15,151.31,133.56,132.85,129.65,
129.30,128.78,128.18,127.94,127.66,124.13,122.43,122.36,121.14,120.66,86.23,86.08,
85.99,85.84,79.90,72.07,71.96,71.84,71.72,62.21,12.15；hrms(esi-tof),
C24h20f2n2o6s, [m+na]=525.0913 (calc.525.0908).
Embodiment 9
The preparation of 1- (2 '-deoxidation -2 ', 2 '-two fluoro-beta-d- erythro forms-furanose) -2- sulfur cytosine
1- (2 '-deoxidation -2 ', 2 '-two fluoro- 3 ', 5 '-dibenzoyl-β-d- erythro form-furanoses) -2- sulfur cytosine (0.2g) is dissolved in
In the methanolic ammonia solution (10ml) of 7n, it is stirred overnight at room temperature, after reaction terminates, removal of solvent under reduced pressure, crude product column chromatography is pure
Change (eluant ch2cl2/ meoh, 95/5, v/v), obtain white foam solid (60mg), yield 52%.
Analytical data:1H-nmr (methanol-d4) δ: 7.89 (d, j=6.0hz, 1h), 7.49 (m, j=8.0,1.6hz, 0h),
6.69-6.61 (m, 1h), 6.27 (d, j=6.0hz, 1h), 4.25 (m, j=12.7,8.7hz, 1h), 4.00 (m, j=7.5,3.5
Hz, 1h), 3.82 (ddd, j=12.5,2.9,1.4hz, 1h), 3.70 (dd, j=12.6,4.3hz, 1h).13c-nmr
(methanol-d4)δ:167.00,163.20,153.91,129.17,126.76,125.35,124.37,123.65,121.95,101.05,
85.12,84.98,84.87,84.73,81.97,81.92,70.52,70.40,70.34,70.21,and 59.55；hrms(esi-tof),
C9h11f2n3o3s, [m+h] +=280.0569 (calc.280.0567).
Embodiment 10
1- (2 '-deoxidation -2 ', 2 '-two fluoro-beta-d- erythro forms-furanose) -2- selenium cytosine
1- (2 '-deoxidation -2 ', 2 '-two fluoro- 3 ', 5 '-dibenzoyl-β-d- erythro form-furanoses) -2- selenium cytosine (0.2g) is dissolved in
In the methanolic ammonia solution (10ml) of 7n, it is stirred overnight at room temperature, after reaction terminates, removal of solvent under reduced pressure, crude product column chromatography is pure
Change (eluant ch2cl2/ meoh, 95/5, v/v), obtain white foam solid (60mg), yield 65%.
Analytical data:1H-nmr (methanol-d4) δ: 7.86 (d, j=6.0hz, 1h), 6.86 (t, j=11.5hz, 1h), 6.27
(d, j=6.0hz, 1h), 4.28-4.16 (m, 1h), 4.05-3.96 (m, 1h), 3.81 (ddd, j=12.5,3.2,1.3hz, 1h),
3.71 (dd, j=12.5,4.5hz, 1h).13c-nmr(methanol-d4)δ:165.41,165.38,163.06,153.83,
126.02,124.32,122.63,101.42,84.99,84.82,84.76,84.59,82.58,82.54,70.63,70.50,70.44,70.31,
and 59.53；Hrms (esi-tof), c9h11f2n3o3se, [m+h] +=328.0014 (calc.328.0012).
Embodiment 11
The preparation of 1- (2 '-deoxidation -2 ', 2 '-two fluoro-beta-d- erythro forms-furanose) -2- deracil
1- (2 '-deoxidation -2 ', 2 '-two fluoro- 3 ', 5 '-dibenzoyl-β-d- erythro form-furanoses) -2- thiourea is added in 25ml reaction bulb
The dense methanolic ammonia solution (5ml) of pyrimidine (0.2g) and 7mol/l, is stirred at room temperature two hours, and reduce pressure precipitation, and crude product divides through post
From purification (eluant ch2cl2/ meoh, 90/10, v/v) pure 1- (2 '-deoxidation -2 ', 2 '-two fluoro-beta-d- erythro forms-furanose) -2-
Deracil (80mg), yield 70%.
Analytical data:1H-nmr (methanol-d4) δ: 7.92 (d, j=6.6hz, 1h), 6.72 (t, j=10.2hz, 1h), 6.24
(d, j=6.6hz, 1h), 4.24-4.29 (m, j=2.4,7.8hz, 1h), 4.03 (m, 1h), 3.82 (dd, j=12.6,2.4hz,
1h), 3.70 (dd, j=12.6,4.8hz, 1h).13c-nmr(methanol-d4)δ:164.94,160.15,152.32,125.28,
123.57,121.86,109.39,85.46,85.32,85.21,85.07,82.94,82.90,70.34,70.22,70.16,70.03,and
59.47；Hrms (esi-tof), c9h10f2n2o4s, [m+na]=303.0230 (calc.303.0227).
Embodiment 12
The preparation of 1- (2 '-deoxidation -2 ', 2 '-two fluoro-beta-d- erythro forms-furanose) -2- sulfur thymus pyrimidine
1- (2 '-deoxidation -2 ', 2 '-two fluoro- 3 ', 5 '-dibenzoyl-β-d- erythro form-furanoses) -2- sulfur breast is added in 25ml reaction bulb
The dense methanolic ammonia solution (5ml) of gland pyrimidine (0.14g) and 7mol/l, is stirred at room temperature two hours, and reduce pressure precipitation, and crude product is through post
Isolate and purify (eluant ch2cl2/ meoh, 90/10, v/v) pure 1- (2 '-deoxidation -2 ', 2 '-two fluoro-beta-d- erythro forms-furan
Sugar) -2- sulfur thymus pyrimidine (40mg), yield 50%.
Analytical data:1H-nmr (methanol-d4) δ: 7.77 (d, j=1.2hz, 1h), 6.67 (t, j=10.2hz, 1h), 4.26
(m, j=13.1,7.9hz, 1h), 4.03 (m, j=7.6,3.1hz, 1h), 3.81 (ddd, j=12.5,3.1,1.3hz, 1h), 3.70
(dd, j=12.6,4.5hz, 1h), 2.00 (d, j=1.2hz, 3h), 1.30 (d, j=9.0hz, 1h).13c-nmr
((methanol-d4)δ:164.67,156.28,149.17,125.27,123.56,121.86,119.68,85.55,85.41,85.30,
85.16,82.87,82.83,70.35,70.22,70.16,70.03,59.46,and 10.96；hrms(esi-tof),
C10h12f2n2o4s, [m+na]=317.0386 (calc.317.0384).
Claims (8)
1. the preparation method of compound shown in formula i,
Wherein, r1And r2It is separately hydroxyl protecting group, preferably benzoyl, trityl, di-substituted-phenyl, second
Acyl group or t-butyldimethylsilyi；r3And r4It is alkyl (preferably c1-c10Alkyl, more preferably methyl, ethyl) or
Halogen (as f, cl or br)；
B is following any group:
Wherein, r5It is hydrogen or alkyl (preferably c1-c10Alkyl, more preferably methyl)；X is hydroxyl or amino；Y be sulfur or
Selenium；
Methods described comprises the steps:
1). compound shown in formula iii is reacted with formula iv or formula vi compound, respectively obtains formula v or formula vii compound；
Wherein,
r1And r2Hydroxyl protecting group independently of one another, preferably benzoyl, trityl, di-substituted-phenyl, acetyl group or
T-butyldimethylsilyi；
r3And r4It is alkyl (preferably c1-c10Alkyl, more preferably methyl, ethyl) or halogen (as f, cl or br)；
r5It is hydrogen or alkyl (preferably c1-c10Alkyl, more preferably methyl)；
X is hydroxyl or amino；Y is sulfur or selenium.
2. the preparation method of compound shown in formula ii,
Wherein, r1And r2It is separately hydroxyl protecting group, preferably benzoyl, trityl, di-substituted-phenyl, second
Acyl group or t-butyldimethylsilyi；r3And r4It is alkyl (preferably c1-c10Alkyl, more preferably methyl, ethyl) or
Halogen (as f, cl or br)；
B is following any group:
Wherein, r5It is hydrogen or alkyl (preferably c1-c10Alkyl, more preferably methyl)；X is hydroxyl or amino；Y be sulfur or
Selenium；
Methods described comprises the steps:
1). compound shown in formula iii is reacted with formula iv or formula vi compound, respectively obtains formula v or formula vii compound；
Wherein,
r1And r2Hydroxyl protecting group independently of one another, preferably benzoyl, trityl, di-substituted-phenyl, acetyl group or
T-butyldimethylsilyi；
r3And r4It is alkyl (preferably c1-c10Alkyl, more preferably methyl, ethyl) or halogen (as f, cl or br)；
r5It is hydrogen or alkyl (preferably c1-c10Alkyl, more preferably methyl)；
X is hydroxyl or amino；Y is sulfur or selenium；
2). formula v that step 1) obtains or formula vii compound are through deprotection base r1, r2After obtain formula ii compound.
3. preparation method according to claim 1 and 2 is it is characterised in that above-mentioned steps 1) in, when formula iv chemical combination
When the x of thing is oh, there are following tautomeric forms:
4. the preparation method according to any one of claim 1-3 is it is characterised in that described step 1) is:
A., in the solution (preferably acetonitrile solution) of compound iv or vi, bsa(is added to be n, o- is double (dimethyl silicon substrate)
Acetamide) reaction after；
B. remove reaction dissolvent, add toluene, compound iii and tmsotf(i.e., TMS triflate),
React at 80 DEG C to 110 DEG C and midbody compound v or vii is obtained；
Above-mentioned steps b are preferably carried out under argon protection.
5. the preparation method according to any one of claim 1-3 is it is characterised in that described step 2) be:
By midbody compound v, vii is dissolved in react in alkali alcosol (as 7n methanolic ammonia solution) and formula ii compound is obtained.
6. preparation method according to claim 1 and 2 is it is characterised in that the preparation method of formula iii compound is as follows:
By compound 2 with bromide reagent (if described bromide reagent is the acetum of 33%hbr) in nonpolar or low pole
In solvent (such as dichloromethane, chloroform or toluene), reaction is obtained compound iii；
Wherein, r1And r2It is hydroxyl protecting group independently of one another, preferably benzoyl, trityl, di-substituted-phenyl, second
Acyl group or t-butyldimethylsilyi；r3And r4It is alkyl (preferably c1-c10Alkyl, more preferably methyl, ethyl) or
Halogen (as f, cl or br)；Lg is mesyloxy (oms), the leaving group such as acetoxyl group (oac).
7. preparation method according to claim 1 and 2 is it is characterised in that the preparation method of formula iv compound is as follows:
By compound 3a(or 3b) with alcohol (such as ethanol, the n-butyl alcohol) solution of thiourea (4) in, in strong organic base (such as
Feldalat NM, Sodium ethylate, n-butyl alcohol sodium, sodium tert-butoxide, potassium tert-butoxide) in the presence of, reaction obtains compound iva, ivb
Or ivc.
8. preparation method according to claim 1 and 2 is it is characterised in that the preparation method of formula iv compound is as follows:
2- chlorine cytosine (compound 5), in the presence of sodium hydrogen selenide, prepares compound ivd.
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| CN102675389A (en) * | 2011-03-08 | 2012-09-19 | 大连大学 | 5-iodine-4-sulfur-2'-deoxyuridine, and derivatives and synthetic method thereof |
| CN102718822A (en) * | 2012-05-18 | 2012-10-10 | 大连大学 | Synthetic method of 4-sulfur thymidine and analogues of 4-sulfur thymidine under microwave irradiation |
| CN103087132A (en) * | 2011-04-07 | 2013-05-08 | 药华医药股份有限公司 | Stereoselective synthesis of beta-nucleosides |
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| CN101130540A (en) * | 2007-09-13 | 2008-02-27 | 上海交通大学 | Nucleoside derivative containing selenium and its preparation method |
| CN102675389A (en) * | 2011-03-08 | 2012-09-19 | 大连大学 | 5-iodine-4-sulfur-2'-deoxyuridine, and derivatives and synthetic method thereof |
| CN103087132A (en) * | 2011-04-07 | 2013-05-08 | 药华医药股份有限公司 | Stereoselective synthesis of beta-nucleosides |
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