CN1886414A - Improved synthesis of 2-substituted adenosines - Google Patents
Improved synthesis of 2-substituted adenosines Download PDFInfo
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- CN1886414A CN1886414A CN 200480035597 CN200480035597A CN1886414A CN 1886414 A CN1886414 A CN 1886414A CN 200480035597 CN200480035597 CN 200480035597 CN 200480035597 A CN200480035597 A CN 200480035597A CN 1886414 A CN1886414 A CN 1886414A
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Abstract
Synthesis of 2-substituted adenosines of formula (I) using 2-nitro pentabenzoyl adenosine, or 2-nitro pentaacetyl adenosine, as intermediate is described: Formula (I) wherein R = C1-6 alkoxy (straight or branched), a phenoxy group (unsubstituted, or mono-, or di-substituted by halo, amino, CF3-, cyano, nitro, C1-6 alkyl, or C1-6 alkoxy), a benzyloxy group (unsubstituted, or mono-, or di-substituted by halo, amino, CF3-, cyano, nitro, C1-6 alkyl, or C1-6 alkoxy), or a benzoyl group (unsubstituted, or mono-, or di-substituted by halo, amino, CF3-,cyano, nitro, C1-6 alkyl, or C1-6 alkoxy). The methods provide improved yield and purity of product.
Description
The present invention relates to the 2-substituted adenosines, for example spongosine (2-methoxy adenosine) is synthetic, and intermediate product synthetic that is used for synthetic this compound.
The sponge of collecting from the Florida seashore in 1945 is isolated natural product spongosine (Bergmann and Feeney, J.Org.Chem.1951,16,981 first in the cryptotethya crypta (Cryptotthiacrypta); Ibid 1956,21, and 226).The reason that spongosine is considered to a kind of uncommon nucleosides is that it is not only first kind of methoxyl group purine finding at nature, and is one of isolating first kind of O-methyl compound from animal tissues.
Reported the method for multiple synthetic sponge nucleosides.First method is by Bergmann and Stempien open (J.Org.Chem.1957,22,1575), and wherein spongosine is by chloro mercury 2-methoxyl group VITAMIN B4 and 2,3, and 5-three-O-benzoyl-D-ribofuranose muriate coupling forms.It is 31% spongosine that this simple coupled reaction provides thick productive rate, with hot water its recrystallization is obtained fusing point then and is shown as 191-191.5 ℃ and the specific rotation spongosine for-43.5 ° (NaOH).
People such as Ojha use the variant of this theme, and (Nucleosides and Nucleotides (1995,14,1889), they are at first with the ribose coupling of 2-ethylenebis dithiocarbamate VITAMIN B4 with suitable protection.Regulate protecting group then and carry out oxidation obtaining a kind of substrate, this substrate and sodium methylate reaction obtain spongosine, and the productive rate of final step is 87%.Prove the purity of the target spongosine after column chromatography is handled by ultimate analysis and fusing point (189-190 ℃).
The chlorine atom of a kind of separation method of modal spongosine by replacing 2-to replace with methylate:
Successfully use the spongosine that this method obtains different productive rates and purity by multiple group: people such as Schaeffer, J.Am.Chem.Soc.1958,80,3738 (35% productive rate, mpt.190-192 ℃); People such as Bartlett, J.Med.Chem.1981,24,947 (productive rate and purity are not provided); People such as Sato, Synth.Proceed.NucleicAcid Chem.1968,1,264.But the shortcoming of this method is that 2-chloro adenosine raw material is difficult to synthesize, so the production cost height.
People such as Cook report that spongosine (J.Org.Chem.1980,45,4020) is for making the by product of isoguanosine generation methylation reaction by methyl iodide.The 1-methyl isoguanosine of expectation and the thick productive rate relatively poor (being respectively 19 and 30%) of spongosine.At first (eluent: chloroform/methanol) the thick spongosine part of purifying, the water recrystallization obtains the sample (7% productive rate is pure) of fusion under 189-192 ℃ then by silica gel column chromatography.
People (Bioorganic ﹠amp such as people such as Deghati (Tetrahedron Letters 41 (2000) 1291-1295) and Wanner; Medicinal Chemistry Letters 10 (2000) 2141-2144) described by being used in the methyl alcohol and handle 2-nitro adenosine pentaacetic acid with potassium cyanide and form spongosine as important by-products in 2-nitro adenosine synthetic.The 2-nitro adenosine productive rate of gained only is 10%, and the spongosine productive rate is 47% productive rate (people such as Deghati).By producing 2-nitro adenosine pentaacetic acid with the nitrated pentaacetic acid adenosine of tetrabutyl ammonium nitrate/trifluoroacetic anhydride (TBAN/TFAA), and people such as () Wanner is by forming adenosine pentaacetic acid (adenosine pentaacetate) with diacetyl oxide and DMAP processing adenosine:
Synthetic according to people's such as Wanner spongosine (2-methoxy adenosine)
Synthetic according to people's such as Wanner spongosine (2-methoxy adenosine)
The shortcoming of this method is that the productive rate or the purity of spongosine is not high.Another kind of shortcoming is that it relates to use toxic agent potassium cyanide.Therefore, expectation provides the alternative method of synthetic sponge nucleosides, and improves the productive rate and the purity of the spongosine that produces.
We have realized that the productive rate and the purity of the spongosine that the method by people such as people such as Deghati and Wanner produces is subjected to multiple effects limit:
I) 2-nitro adenosine pentaacetic acid is polluted by TBAN.It disturbs the methoxylation and the deprotection (also is like this if use tetramethyl-ammonium nitrate (TMAN) to replace the TBAN situation) of 2-nitro adenosine pentaacetic acid subsequently, and influences spongosine degree of purity of production and productive rate unfriendly.This situation has problem especially, because TBAN is an amphoteric, and can not remove by water treatment.In addition, owing to the partial solubility of 2-nitro adenosine pentaacetic acid at water layer, wherein some may be lost by water treatment.
Ii) only produce adenosine pentaacetic acid intermediate product with low-yield and purity.We find that tetrem acidylate precursor exists as main by product.
Iii) the pentaacetic acid ester group of penta-acetyl compound is labile, and this causes these compound decomposition to become tetra-acetylated compound.For example, we pass through column chromatography purifying adenosine pentaacetic acid, but evidence suggests that this compound decomposes in this process.With the not success of trial of this compound recrystallization, and it is unbodied rather than crystallization in essence.
We are surprisingly found out that, can improve the purity and the productive rate of spongosine and other 2-substituted adenosines greatly by using the benzoyl protecting group.
According to the present invention, the synthetic method of the 2-substituted adenosines of a kind of formula I is provided, described method comprises 2-nitro pentaphene formyl radical adenosine is changed into the 2-substituted adenosines:
R=C wherein
1-6Alkoxyl group (straight or branched), phenoxy group (are not substituted, perhaps by halogen, amino, CF
3-, cyano group, nitro, C
1-6Alkyl or C
1-6Alkoxyl group one or two replaces), benzyloxy (is not substituted, perhaps by halogen, amino, CF
3-, cyano group, nitro, C
1-6Alkyl or C
1-6Alkoxyl group one or two replaces), or benzoyl (is not substituted, perhaps by halogen, amino, CF
3-, cyano group, nitro, C
1-6Alkyl or C
1-6Alkoxyl group one or two replaces).
Preferred R=methoxyl group, oxyethyl group, propoxy-, butoxy, pentyloxy, hexyloxy, phenoxy group, benzyloxy or benzoyl.
We find, compare with 2-nitro adenosine pentaacetic acid, and 2-nitro-pentaphene formyl radical adenosine has increased organic solubleness, stability and crystallinity.Therefore, 2-nitro-pentaphene formyl radical adenosine is handled easily than 2-nitro adenosine pentaacetic acid, and can be with productive rate and the purity preparation higher than this compound.Therefore the productive rate and the purity of the spongosine that is produced also improve.Use 2-nitro-pentaphene formyl radical adenosine also can high yield as intermediate product and purity produce other 2-substituted adenosines.
Preferably by making 2-nitro-pentaphene formyl radical adenosine and suitable negatively charged ion (C for example
1-6Alkoxide anion or phenol salt anion), perhaps by with 2-nitro-pentaphene formyl radical adenosine deprotection and with suitable negatively charged ion (C for example
1-6Alkoxide anion or phenol salt anion) reaction 2-nitro-pentaphene formyl radical adenosine is changed into the 2-substituted adenosines.Be the synthetic sponge nucleosides, can realize, describe as people such as people such as Deghati and Wanner by reacting with potassium cyanide and methyl alcohol.But, preferably use the less methylate negatively charged ion source of toxicity.Preferred source is MeOH/NaOMe, MeOH/n-BuLi, MeOH/NaOH, MeOH/NaH or MeOH/KO
tBu.
The method of preferred methoxylation 2-nitro-pentaphene formyl radical adenosine is described in following examples 4.
The 2-substituted adenosines of other formula I can be by using sodium hydroxide, sodium hydride, butyllithium or KO
tBu and suitable alcohol (C for example
1-6Alcohol or phenol) handle 2-nitro-pentaphene formyl radical adenosine and prepare.KO
tBu can use with phenol.
According to the present invention, also provide 2-nitro pentaphene formyl radical adenosine.
The present invention also provides the application of 2-nitro pentaphene formyl radical adenosine in the 2-of formula I substituted adenosines is synthetic.
The preferred method of the present invention also comprises pentaphene formyl radical adenosine is changed into 2-nitro-pentaphene formyl radical adenosine.
According to a further aspect in the invention, provide the synthetic method of the 2-substituted adenosines of 2-nitro-pentaphene formyl radical adenosine or formula I, described method comprises pentaphene formyl radical adenosine is changed into 2-nitro-pentaphene formyl radical adenosine.
Can be by using suitable nitrating agent, for example tetrabutyl ammonium nitrate (TBAN) or tetramethyl-ammonium nitrate (TMAN) change into 2-nitro-pentaphene formyl radical adenosine with pentaphene formyl radical adenosine.
The preferred TBAN or TMAN and trifluoroacetic anhydride (TBAN/TFAA or TMAN/TFAA) of using carries out nitrated.Preferred TBAN/TFAA or TMAN/TFAA are in the methylene dichloride (DCM).
Compare with 2-nitro adenosine pentaacetic acid, 2-nitro-pentaphene formyl radical adenosine improves organic solubleness and degree of crystallinity.A specific advantages of these character is to compare with 2-nitro adenosine pentaacetic acid, by water treatment, preferably carrying out recrystallization subsequently can remove many or all TBAN or TMAN from 2-nitro-pentaphene formyl radical adenosine.Preferred TMAN rather than the TBAN of using removes than TBAN is easier because we have found that TMAN as nitrating agent.Preferably in water treatment, carry out 3-5 washing, and preferably carry out recrystallization 2 or 3 times.
For example, can be by compound being dissolved in organic solvent (for example ethyl acetate or DCM), and wash 2-nitro-pentaphene formyl radical adenosine that the solution of gained comes water treatment to produce with water.Usually, three washings of the minimum needs of vast scale TBAN or TMAN have been found to remove.But, carry out 5 washings usually to guarantee removing TBAN or TMAN as much as possible.
Wash solution with water, 2-nitro-pentaphene formyl radical adenosine is being dissolved in EtOAc/ ethanol or methylene dichloride/ethanol, and can carry out recrystallization by removing organic solvent after the 2-of solution weight crystallization from then on nitro-pentaphene formyl radical adenosine.
We find, and the crude product that carries out nitration reaction with TBAN/TFAA can not recrystallization, because there is a large amount of TBAN.But, can be with EtOAc or CH after water treatment
2Cl
2With the alcoholic acid mixture easily with the compound recrystallization.Also may have the impurity except that TBAN after treatment process in the mixture, these impurity can be removed by recrystallization.A minimum recrystallization may be enough, but may need sometimes twice or three recrystallizations to remove these impurity satisfactorily.
Compare with the penta-acetyl compound, the increase of the organic solubleness of pentaphene formylation compound guarantees by water treatment and recrystallization a small amount of compound forfeiture is only arranged.
The method of preferred nitrated pentaphene formyl radical adenosine is described in following examples 2 and 3.
The preferred method of the present invention also comprises adenosine is changed into pentaphene formyl radical adenosine.
The present invention also provides the synthetic method of the 2-substituted adenosines of pentaphene formyl radical adenosine, 2-nitro-pentaphene formyl radical adenosine or formula I, and described method comprises adenosine is changed into pentaphene formyl radical adenosine.
Can be by using suitable benzoylation reagent, for example Benzoyl chloride changes into pentaphene formyl radical adenosine with adenosine.Also should use suitable alkali, for example pyridine.Dimethyl formamide (DMF) can be used as solvent, but preferably adenosine is dissolved/be suspended in the pyridine, because this obtains the result of cleaning.
The method of preferred benzoylation adenosine is described in following examples 1.
Using an advantage of pentaphene formyl radical adenosine is that it can be than the easier purifying of adenosine pentaacetic acid.For example by water treatment, recrystallization purifying pentaphene formyl radical adenosine then.This purifying than the adenosine pentaacetic acid that relates to column chromatography is more desirable, in described column chromatography process, some decomposition or the forfeiture of product takes place.
The present invention also provides the application of pentaphene formyl radical adenosine in the 2-substituted adenosines of 2-nitro pentaphene formyl radical adenosine or formula I is synthetic.
The present invention also provides the application of benzoylation reagent in the 2-of formula I substituted adenosines is synthetic.
The present invention also provides by the inventive method synthetic 2-substituted adenosines, 2-nitro pentaphene formyl radical adenosine or pentaphene formyl radical adenosine.
Compare with people's such as people such as the Deghati that uses the ethanoyl protecting group and Wanner currently known methods, method of the present invention allows more easily synthetic product, and productive rate and purity are higher.We have realized that it is former because organic solubleness of employed compound, stability and crystallinity increase among the present invention.
According to an alternative aspect of the present invention, the synthetic method of the 2-substituted adenosines of a kind of formula I is provided, described method comprises: with TBAN or the nitrated adenosine pentaacetic acid of TMAN to produce 2-nitro adenosine pentaacetic acid; Reduce the TBAN of pollution 2-nitro adenosine pentaacetic acid or the amount of TMAN; Produce the 2-substituted adenosines by 2-nitro adenosine pentaacetic acid then:
R=C wherein
1-6Alkoxyl group (straight or branched), phenoxy group (are not substituted, perhaps by halogen, amino, CF
3-, cyano group, nitro, C
1-6Alkyl or C
1-6Alkoxyl group one or two replaces), benzyloxy (is not substituted, perhaps by halogen, amino, CF
3-, cyano group, nitro, C
1-6Alkyl or C
1-6Alkoxyl group one or two replaces), or benzoyl (is not substituted, perhaps by halogen, amino, CF
3-, cyano group, nitro, C
1-6Alkyl or C
1-6Alkoxyl group one or two replaces).
Preferred R is methoxyl group, oxyethyl group, propoxy-, butoxy, pentyloxy, hexyloxy, phenoxy group, benzyloxy or benzoyl.
Be surprisingly found out that the method for a kind of TBAN of effectively reducing and TMAN pollutent is to grind 2-nitro adenosine pentaacetic acid with Virahol, washes with water then.This can improve the purity and the productive rate of spongosine or other 2-substituted adenosines significantly.
The present invention also provides a kind of method that reduces the amount of the TBAN that pollutes 2-nitro adenosine pentaacetic acid or TMAN, described 2-nitro adenosine pentaacetic acid is by forming with TBAN or the nitrated adenosine pentaacetic acid of TMAN, described method comprises with Virahol grinds 2-nitro adenosine pentaacetic acid, and washes the amount of the 2-nitro adenosine pentaacetic acid of grinding with reduction TBAN or TMAN with water.
The present invention also provides the 2-nitro adenosine pentaacetic acid that is produced by this method.
Preferably carry out nitrated with TBAN or TMAN and trifluoroacetic anhydride (TBAN/TFAA or TMAN/TFAA).Preferred TBAN/TFAA or TMAN/TFAA are in methylene dichloride (DCM).The nitrifying method of preferred adenosine pentaacetic acid is described in following examples 5.
Can be by with 2-nitro adenosine pentaacetic acid deprotection, and with suitable negatively charged ion (C for example
1-6Alkoxide anion or phenol salt anion) reaction 2-nitro adenosine pentaacetic acid is changed into the 2-substituted adenosines.Be the synthetic sponge nucleosides, can realize, describe as people such as people such as Deghati and Wanner by reacting with potassium cyanide and methyl alcohol.But, preferably use the less methylate negatively charged ion source of toxicity.Preferred source is MeOH/NaOMe, MeOH/n-BuLi, MeOH/NaOH, MeOH/NaH or MeOH/KO
tBu.The method that preferably 2-nitro adenosine pentaacetic acid is changed into spongosine is described in following examples 5.It is believed that can be by using suitable C
2-6Alcohol or phenol and sodium-hydroxide treatment 2-nitro adenosine pentaacetic acid synthesize other 2-substituted adenosines.
Another aspect of the present invention provides the method for synthetic sponge nucleosides, and described method comprises with MeOH/NaOMe, MeOH/n-BuLi, MeOH/NaOH or MeOH/NaH handles 2-nitro adenosine pentaacetic acid to form spongosine.
The present invention also provides the 2-substituted adenosines of a kind of formula I, does not comprise the synthetic method of spongosine, and described method comprises 2-nitro adenosine pentaacetic acid deprotection, and and C
2-6Alkoxide anion or phenol salt anion reaction.It is believed that this can by with suitable C
2-6Alcohol or phenol and sodium hydroxide (or NaH, BuLi or KO
tBu) reaction realizes.
Method of the present invention also comprises adenosine is changed into the adenosine pentaacetic acid.This can realize by the method that people such as people such as Deghati and Wanner describe.But we have realized that and make the adenosine pentaacetic acid that only produces low-yield and purity in this way, and tetrem acidylate precursor exists as main by product.
We have found that; if method of the present invention also comprises adenylylation to form the O-triacetyl and/or the tetra-acetylated derivative of adenosine; separate derivative; and with isolating derivative acidylate to produce adenosine pentaacetic acid intermediate product, then can improve the productive rate and the purity of 2-substituted adenosines product.
Another aspect of the present invention provides the synthetic method of the 2-substituted adenosines of a kind of adenosine pentaacetic acid, 2-nitro adenosine pentaacetic acid or formula I; said method comprising the steps of: the acidylate adenosine is to form the O-triacetyl and/or the tetra-acetylated derivative of adenosine; separate derivative, and isolating derivative acidylate is produced the adenosine pentaacetic acid.
Can separate O-triacetyl and/or tetra-acetylated derivative with column chromatography.
Then can nitrated adenosine to form 2-nitro adenosine pentaacetic acid.2-nitro adenosine pentaacetic acid can be transformed the 2-substituted adenosines of accepted way of doing sth I then, for example use method of the present invention.
We find that also the 5th acetate groups of penta-acetyl compound is variable, and this causes these compound decomposition to become tetra-acetylated compound.For example, we pass through column chromatography purifying adenosine pentaacetic acid, but evidence suggests that this compound decomposes in this process.With the not success of trial of this compound recrystallization, and it is unbodied rather than crystallization in essence.
We have realized that, if method of the present invention comprises alternatively or extraly that also washing adenosine pentaacetic acid intermediate product is to reduce the amount of contaminative adenosine tetraacethyl, the adenosine pentaacetic acid of nitrated washing then then can improve the productive rate and the purity of 2-substituted adenosines product.
Another aspect of the present invention also provides the synthetic method of the 2-substituted adenosines of a kind of adenosine pentaacetic acid, 2-nitro adenosine pentaacetic acid or formula I, said method comprising the steps of: with the acylated derivatives acidylate of adenosine or adenosine to form the adenosine pentaacetic acid; And washing adenosine pentaacetic acid is to reduce the amount of contaminative adenosine tetraacethyl.
For washing adenosine pentaacetic acid, preferably it is dissolved in chloroform, and washs with acetic acid solution (preferred 1M).
Then that the adenosine pentaacetic acid is nitrated to form 2-nitro adenosine pentaacetic acid.Then 2-nitro adenosine pentaacetic acid is transformed the 2-substituted adenosines of accepted way of doing sth I, for example use method of the present invention.
It is believed that 2-nitro adenosine pentaacetic acid may be deleterious.Therefore, may expect to guarantee that the 2-substituted adenosines that is produced by 2-nitro adenosine pentaacetic acid is polluted by the least possible 2-nitro adenosine pentaacetic acid.According to the present invention, this can be by changing into 2-nitro adenosine pentaacetic acid 2-chloro adenosine pentaacetic acid, then 2-chloro adenosine pentaacetic acid being changed into the 2-substituted adenosines and realize.
It is believed that 2-nitro adenosine pentaacetic acid to the conversion of 2-chloro adenosine pentaacetic acid can be by realizing the chlorination of 2-nitro adenosine pentaacetic acid with suitable chlorination reagent, for example ammonium chloride.
Another aspect of the present invention provides the synthetic method of the 2-substituted adenosines of a kind of formula I, and described method comprises 2-chloro adenosine pentaacetic acid is changed into the 2-substituted adenosines.
The present invention also provides the application of five acetylize 2-chloro adenosines in 2-substituted adenosines synthetic.
It is believed that can be by with 2-chloro adenosine pentaacetic acid deprotection, and with suitable negatively charged ion (C for example
1-6Alkoxide anion or phenol salt anion) reaction and 2-chloro adenosine pentaacetic acid is changed into the 2-substituted adenosines.Be the synthetic sponge nucleosides, it is believed that it can realize by reacting with potassium cyanide and methyl alcohol, describe as people such as people such as Deghati and Wanner.But, preferably use the less methylate negatively charged ion source of toxicity.Preferred source is MeOH/NaOMe, MeOH/n-BuLi, MeOH/NaOH or MeOH/NaH.It is believed that and to use suitable C
2-6Alcohol or phenol and sodium hydroxide (or BuLi, NaH or KO
tBu) synthetic other 2-substituted adenosines.
The present invention also provides the 2-substituted adenosines of formula I, or is used for the intermediate product of the 2-substituted adenosines of synthesis type I, and they are by method production of the present invention.
Method of the present invention can be used for high yield and purity Synthetic 2-substituted adenosines.For example, we can synthesize the spongosine of purity＞96%.
The present mode to exemplify is only described embodiment of the present invention with reference to the scheme 1 and 2 of the method for the appended preferred Synthetic 2-methoxy adenosine of demonstration (spongosine).
Embodiment 1
The preparation of pentaphene formyl radical adenosine:
To at pyridine (20cm
3) in adenosine (2.00g, 7.47mmol) suspension/solution adds Benzoyl chloride (7.35g, 6.07cm
3, 52.29mmol).Heated 4 hours down at 65 ℃, with reaction mixture impouring ethanol (20cm
3).Remove under the vacuum and desolvate.With DCM (300cm
3) the distribution residuum, water (100cm
3) washing, with DCM (3 * 50cm
3) the washing water layer, merge organic layer, and water (2 * 100cm
3), salt solution (100cm
3) washing, dry (MgSO
4).Remove under the vacuum and desolvate, come the purifying resistates, obtain target product (5.660g, 96.2%), be a kind of colorless solid with acetone/EtOH recrystallization.LCMS：788(M+H)。
Embodiment 2
Use the preparation of TMAN/TFAA as the 2-nitro-pentaphene formyl radical adenosine of nitrating agent:
To at DCM (40cm
3) in tetramethyl-ammonium nitrate (1.37g, 11.4mmol) suspension adds trifluoroacetic anhydride (2.40g, 1.62cm
3, 11.4mmol).Stirred 1.5 hours under the room temperature, be cooled to 0 ℃, and be added in DCM (50cm
3) in pentaphene formyl radical adenosine (6.00g, solution 7.62mmol)., to room temperature, under vacuum, remove desolvate [the rotatory evaporator bath temperature remains on 30 ℃ or lower] at 14 hours internal heating.Residuum is dissolved in EtOAc (200cm
3), water (3 * 150cm
3), salt solution (50cm
3) washing, dry (MgSO
4).Under vacuum, remove and desolvate, come the purifying resistates, obtain target product (5.59g, 88.2%), be a kind of pale solid with DCM/EtOH recrystallization (twice).
1HNMR (400MHz, CDCl
3): 4.79dd, J=11.5,4.2Hz), 4.92 (2H, m), 6.08 (1H, J=5.6Hz), 6.16 (1H, dd, J=5.8,4.4Hz), 6.57 (1H, J=5.4Hz), 7.39 (10H, m), 7.55m), 7.85 (4H, m), 7.92 (2H, m), 8.04 (4H is m) with 8.44 (1H, s) .LCMS:833 (M+H) and 855 (M+Na).
Embodiment 3
Use the preparation of TBAN/TFAA as the 2-nitro-pentaphene formyl radical adenosine of nitrating agent
To at DCM (20cm
3) in tetrabutyl ammonium nitrate (1.16g, 3.81mmol) solution adds trifluoroacetic anhydride (0.80g, 0.538cm
3, 3.81mmol).0 ℃ was stirred 0.5 hour down, be added in DCM (20cm then under 0 ℃
3) in pentaphene formyl radical adenosine (2.00g, solution 2.54mmol) (optional cover reaction vessel) with silver foil.Heating is 14 hours under the room temperature, with reaction mixture impouring ice/water, and the separation water layer, and with DCM (40cm
3) extraction, merge organic layer, under vacuum, remove desolvate [the rotatory evaporator bath temperature is remained on 30 ℃ or lower].Resistates is dissolved in EtOAc (150cm
3), water (5 * 75cm
3), salt solution (50cm
3) washing, dry (MgSO
4).Under vacuum, remove and desolvate, come the purifying resistates, obtain target product (1.604g, 75.9%), be a kind of lark solid with DCM/EtOH recrystallization (twice).
1H NMR (400MHz, CDCl
3): 4.79 (1H, dd, J=11.5,4.2Hz), 4.92 (2H, m), 6.08 (1H, t, J=5.6Hz), 6.16 (1H, dd, J=5.8,4.4Hz), 6.57 (1H, d, J=5.4Hz), 7.39 (10H, m), 7.55 (5H, m), 7.85 (4H, m), 7.92 (2H, m), 8.04 (4H, m) and 8.44 (1H, s) .LCMS:833 (M+H) and 855 (M+Na).
Embodiment 4
The preparation of 2-methoxy adenosine (spongosine):
To at MeOH (10cm
3) in 2-nitro-pentaphene formyl radical adenosine (0.52g is added in MeOH (10cm in suspension 0.62mmol)
3) in NaOH (0.15g, solution 3.70mmol).Stirred 16 hours under the room temperature, obtain a kind of red solution.Under vacuum, remove and desolvate, resistates is water-soluble, with 0.2MHCl neutralization (dropping) to prevent excessive acidifying and the depurination that causes thereof.Under vacuum, remove and desolvate, resistates is dissolved in MeOH: Water (1: 1) (about 40cm
3) [needing heating], reaction mixture is placed spend the night (20 ℃) in water cooler.Target product is precipitated out from reaction mixture, filters and obtains title compound (0.100g, 54%), is a kind of lark solid.LCMS:298 (M+H), small amount of impurities 329 (M+H).Can carry out further purifying with reverse-phase chromatography.
1HNMR (400MHz, CDCl
3): 3.52 (1H, m), 3.60 (1H, m), 3.78 (3H, s), 3.89 (1H, dd, J=7.2,3.9Hz), 4.12 (1H, m), 4.56 (1H, dd, J=11.3,6.1Hz), 5.10 (1H, m), 5.11 (1H, d, J=4.7Hz), 5.35 (1H, d, J=6.2Hz), 5.75 (1H, d, J=6.2Hz), 7.27 (2H, br.s) and 8.11 (1H, s).
Embodiment 5
The system of adenosine pentaacetic acid is put forth energy
To the adenosine in diacetyl oxide (10mL) (1.0g, 3.74mmol) solution add sodium hydride (60%, in mineral oil, 0.9g, 22.5mmol), and with mixture in 110 ℃ of heating 20 hours down.Reaction mixture is cooled to room temperature, then impouring ice/NaHCO
3(250mL).Add EtOAc (150mL), and water (3 * 100cm
3) the washing organic layer, dry (MgSO
4), and under vacuum, remove and desolvate.With silica gel chromatography (silica gel 60) purifying crude product, use EtOAc: heptane (1: 1), increase to the EtOAc wash-out, obtain target product (0.6g, 31%).
The preparation of 2-nitro-adenosine pentaacetic acid
(642mg, (0.68mL 4.72mmol), and at room temperature stirred the suspension of gained 1 hour, was cooled to 0 ℃ then to add trifluoroacetic anhydride in suspension 4.72mmol) to the tetramethyl-ammonium nitrate in DCM (10mL).Be added in adenosine pentaacetic acid among the DCM (10mL) (1.50g, solution 3.14mmol), and in 2.5 hours, solution is heated to room temperature.With salt water washing crude product, dry (MgSO
4), and under vacuum, obtain target product except that desolvating, be a kind of beige solid foam (1.36g, 83%).
The system of 2-methoxy adenosine (spongosine) is put forth energy
(71mg 1.3mmol), and stirs mixture 3 hours to add NaOMe at the solution (in MeOH) of 2-nitro-adenosine pentaacetic acid (275mg.0.53mmol) under the room temperature.(70mg 1.3mmol), and concentrates reaction mixture and to obtain a kind of yellow oil under vacuum to add ammonium chloride.With silica gel chromatography purifying crude product, use EtOAc, increase to EtOAc: MeOH (15: 1) wash-out, obtain target product with the Virahol recrystallization then, be a kind of white solid (70mg, 47%).
Can preferably use citric acid solution or 0.2HCL to replace ammonium chloride.
Scheme 1
Scheme 2
Claims (44)
1. the synthetic method of the 2-substituted adenosines of formula I, described method comprise 2-nitro-pentaphene formyl radical adenosine are changed into the 2-substituted adenosines:
R=C wherein
1-6Alkoxyl group (straight or branched), phenoxy group (are not substituted, perhaps by halogen, amino, CF
3-, cyano group, nitro, C
1-6Alkyl or C
1-6Alkoxyl group one or two replaces), benzyloxy (is not substituted, perhaps by halogen, amino, CF
3-, cyano group, nitro, C
1-6Alkyl or C
1-6Alkoxyl group one or two replaces), or benzoyl (is not substituted, perhaps by halogen, amino, CF
3-, cyano group, nitro, C
1-6Alkyl or C
1-6Alkoxyl group one or two replaces).
2. according to the process of claim 1 wherein R=methoxyl group, oxyethyl group, propoxy-, butoxy, pentyloxy, hexyloxy, phenoxy group, benzyloxy or benzoyl.
3. according to the method for claim 1 or 2, wherein pass through deprotection and and C
1-6Alkoxide anion or phenol salt anion reaction change into the 2-substituted adenosines with 2-nitro-pentaphene formyl radical adenosine.
4. according to the method for claim 3, wherein said negatively charged ion is by MeOH/NaOMe, MeOH/n-BuLi, MeOH/NaOH, MeOH/NaH or MeOH/KO
tThe methylate negatively charged ion that Bu produces.
5. according to the method for any aforementioned claim, described method also comprises pentaphene formyl radical adenosine is changed into 2-nitro-pentaphene formyl radical adenosine.
6.2-the synthetic method of nitro-pentaphene formyl radical adenosine, described method comprise pentaphene formyl radical adenosine is changed into 2-nitro-pentaphene formyl radical adenosine.
7. according to the method for claim 5 or 6, wherein use tetrabutyl ammonium nitrate (TBAN) or tetramethyl-ammonium nitrate (TMAN) pentaphene formyl radical adenosine to be changed into 2-nitro-pentaphene formyl radical adenosine as nitrating agent.
8. according to the method for claim 7, described method reduces 2-nitro-TBAN of pentaphene formyl radical adenosine or the amount of TMAN polluted after also being included in nitration reaction.
9. method according to Claim 8 wherein reduces the amount of TBAN or TMAN by washing 2-nitro-pentaphene formyl radical adenosine with water.
10. according to the method for claim 9, after described method also is included in and washes with water with 2-nitro-pentaphene formyl radical adenosine recrystallization.
11. according to the method arbitrarily of claim 5-10, described method also comprises adenosine is changed into pentaphene formyl radical adenosine.
12. the synthetic method of pentaphene formyl radical adenosine or 2-nitro-pentaphene formyl radical adenosine, described method comprise adenosine is changed into pentaphene formyl radical adenosine.
13. according to the method for claim 11 or 12, wherein with Benzoyl chloride with the adenosine benzoylation.
14.2-nitro pentaphene formyl radical adenosine.
15.2-the application of nitro pentaphene formyl radical adenosine in the 2-of formula I substituted adenosines is synthetic.
16. the application of pentaphene formyl radical adenosine in the 2-substituted adenosines of 2-nitro-pentaphene formyl radical adenosine or formula I is synthetic.
17. the application of benzoyl reagent in the 2-of formula I substituted adenosines is synthetic.
18. the method for the TBAN of reduction pollution 2-nitro pentaphene formyl radical adenosine or the amount of TMAN; described 2-nitro pentaphene formyl radical adenosine is by using TBAN or the nitrated pentaphene formyl radical of TMAN adenosine to form, and described method comprises and washes 2-nitro-pentaphene formyl radical adenosine with water.
19. according to the method for claim 18, after described method also is included in and washes with water with 2-nitro-pentaphene formyl radical adenosine recrystallization.
20. the synthetic method of the 2-substituted adenosines of formula I, described method comprises: produce 2-nitro adenosine pentaacetic acid with tetrabutyl ammonium nitrate (TBAN) or the nitrated adenosine pentaacetic acid of tetramethyl-ammonium nitrate (TMAN); Reduce the TBAN of pollution 2-nitro adenosine pentaacetic acid or the amount of TMAN; Produce the 2-substituted adenosines by 2-nitro adenosine pentaacetic acid then:
R=C wherein
1-6Alkoxyl group (straight or branched), phenoxy group (are not substituted, perhaps by halogen, amino, CF
3-, cyano group, nitro, C
1-6Alkyl or C
1-6Alkoxyl group one or two replaces), benzyloxy (is not substituted, perhaps by halogen, amino, CF
3-, cyano group, nitro, C
1-6Alkyl or C
1-6Alkoxyl group one or two replaces), or benzoyl (is not substituted, perhaps by halogen, amino, CF
3-, cyano group, nitro, C
1-6Alkyl or C
1-6Alkoxyl group one or two replaces).
21., wherein reduce the amount of TBAN or TMAN pollutent by the 2-nitro adenosine pentaacetic acid that grinds 2-nitro adenosine pentaacetic acid with Virahol and wash grinding with water according to the method for claim 20.
22., wherein pass through with 2-nitro adenosine pentaacetic acid deprotection and and C according to the method for claim 20 or 21
1-6Alkoxide anion or phenol salt anion reaction are produced the 2-substituted adenosines by 2-nitro adenosine pentaacetic acid.
23. according to the method arbitrarily of claim 20-22, wherein this 2-substituted adenosines is the 2-methoxy adenosine, and it be by with from methyl alcohol/NaOMe, methyl alcohol/n-BuLi, methyl alcohol/NaOH, methyl alcohol/NaH or methyl alcohol/KO
tThe methylate anionic reactive of Bu is produced by 2-nitro adenosine pentaacetic acid.
24. according to the method for item arbitrarily of claim 20-23, described method also comprises by the acidylate adenosine comes the synthesizing adenosine pentaacetic acid.
25., wherein adenylylation is formed the O-triacetyl and/or the tetra-acetylated derivative of adenosine, this derivative is separated, and isolating derivative acidylate is produced the adenosine pentaacetic acid according to the method for claim 24.
26. according to the method for claim 24 or 25, described method also comprises washing adenosine pentaacetic acid to remove contaminative adenosine tetraacethyl, the adenosine pentaacetic acid of nitrated washing is to form 2-nitro adenosine pentaacetic acid then.
27. the synthetic method of the 2-substituted adenosines of formula I; described method comprises O-triacetyl and/or the tetra-acetylated derivative that adenylylation is formed adenosine; separate this derivative, the isolating derivative of acidylate to be producing the adenosine pentaacetic acid, and produces the 2-substituted adenosines by the adenosine pentaacetic acid.
28. according to the method for claim 27, described method also comprises the amount of washing adenosine pentaacetic acid with reduction contaminative adenosine tetraacethyl, produces the 2-substituted adenosines by the adenosine pentaacetic acid of this washing then.
29. the synthetic method of the 2-substituted adenosines of formula I; described method comprises that the acylated derivatives of acidylate adenosine or adenosine is to form the adenosine pentaacetic acid; wash the amount of adenosine pentaacetic acid, and produce the 2-substituted adenosines by the adenosine pentaacetic acid of this washing with reduction contaminative adenosine tetraacethyl.
30. according to the method for item arbitrarily of claim 27-29, described method also comprises the nitrated generation of adenosine pentaacetic acid 2-nitro adenosine pentaacetic acid, and produces the 2-substituted adenosines by 2-nitro adenosine pentaacetic acid.
31. according to the method for claim 30, wherein the 2-substituted adenosines is the 2-methoxy adenosine, and it is by making from methyl alcohol/NaOMe, methyl alcohol/n-BuLi, methyl alcohol/NaOH, methyl alcohol/NaH or methyl alcohol/KO
tThe methylate negatively charged ion of Bu and the reaction of 2-nitro adenosine pentaacetic acid produce.
32. according to claim 20,21 or 30 method arbitrarily, described method also comprises 2-nitro adenosine pentaacetic acid is changed into 2-chloro adenosine pentaacetic acid, produces the 2-substituted adenosines by 2-chloro adenosine pentaacetic acid then.
33.2-the synthetic method of substituted adenosines, described method comprise 2-chloro adenosine pentaacetic acid is changed into the 2-substituted adenosines.
34. according to the method for claim 33, described method also comprises by 2-nitro adenosine pentaacetic acid produces 2-chloro adenosine pentaacetic acid.
35. the method for item arbitrarily according to claim 32-34, wherein this 2-substituted adenosines is the 2-methoxy adenosine, and by with from the methylate negatively charged ion of methyl alcohol/NaOMe, methyl alcohol/n-BuLi, methyl alcohol/NaOH or methyl alcohol/NaH and the reaction of 2-nitro adenosine pentaacetic acid and 2-chloro adenosine pentaacetic acid is changed into the 2-methoxy adenosine.
36. by the method synthetic 2-substituted adenosines of item arbitrarily according to claim 20-35.
37.2-comprising, the synthetic method of methoxy adenosine, described method make from methyl alcohol/NaOMe, methyl alcohol/n-BuLi, methyl alcohol/NaOH, methyl alcohol/NaH or methyl alcohol/KO
tThe methylate negatively charged ion of Bu and the reaction of 2-nitro adenosine pentaacetic acid.
38.2-the synthetic method of methoxy adenosine, described method is included in the step shown in scheme 1 or 2.
39.2-the synthetic method of methoxy adenosine, described method are basically as described.
40. the 2-methoxy adenosine of purity＞96%.
Produce 2-nitro adenosine pentaacetic acid 41.2-the synthetic method of nitro adenosine pentaacetic acid, described method comprise with TBAN or the nitrated adenosine pentaacetic acid of TMAN, and reduce the TBAN of pollution 2-nitro adenosine pentaacetic acid or the amount of TMAN.
42. according to the method for claim 41, wherein by grinding 2-nitro adenosine pentaacetic acid with Virahol, and the 2-nitro adenosine pentaacetic acid that washes grinding with water reduces the amount of TBAN or TMAN pollutent.
43. the synthetic method of the 2-substituted adenosines of adenosine pentaacetic acid, 2-nitro adenosine pentaacetic acid or formula I; said method comprising the steps of: the acidylate adenosine is to form the O-triacetyl and/or the tetra-acetylated derivative of adenosine; separate this derivative, and the isolating derivative of acidylate is to produce the adenosine pentaacetic acid.
44. the synthetic method of the 2-substituted adenosines of adenosine pentaacetic acid, 2-nitro adenosine pentaacetic acid or formula I said method comprising the steps of: the acylated derivatives of acidylate adenosine or adenosine is to form the adenosine pentaacetic acid; And washing adenosine pentaacetic acid is to reduce the amount of contaminative adenosine tetraacethyl.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB0328319A GB0328319D0 (en) | 2003-12-05 | 2003-12-05 | Improved synthesis of 2-substituted adenosines |
| GB0328321.5 | 2003-12-05 | ||
| GB0328319.9 | 2003-12-05 |
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| Publication Number | Publication Date |
|---|---|
| CN1886414A true CN1886414A (en) | 2006-12-27 |
| CN100455591C CN100455591C (en) | 2009-01-28 |
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| CN (1) | CN100455591C (en) |
| GB (1) | GB0328319D0 (en) |
| NO (1) | NO20063109L (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103333215A (en) * | 2013-07-01 | 2013-10-02 | 淮海工学院 | Synthetic method of 2-fluoroadenosine |
| CN108570078A (en) * | 2018-07-18 | 2018-09-25 | 荆门医药工业技术研究院 | A method of preparing three-O- benzoyls-β of 1-O- acetyl group -2,3,5--D-RIBOSE |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB9301000D0 (en) * | 1993-01-20 | 1993-03-10 | Glaxo Group Ltd | Chemical compounds |
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2003
- 2003-12-05 GB GB0328319A patent/GB0328319D0/en not_active Ceased
-
2004
- 2004-12-03 CN CNB2004800355978A patent/CN100455591C/en not_active Expired - Fee Related
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2006
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103333215A (en) * | 2013-07-01 | 2013-10-02 | 淮海工学院 | Synthetic method of 2-fluoroadenosine |
| CN108570078A (en) * | 2018-07-18 | 2018-09-25 | 荆门医药工业技术研究院 | A method of preparing three-O- benzoyls-β of 1-O- acetyl group -2,3,5--D-RIBOSE |
Also Published As
| Publication number | Publication date |
|---|---|
| NO20063109L (en) | 2006-09-05 |
| CN100455591C (en) | 2009-01-28 |
| GB0328319D0 (en) | 2004-01-07 |
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