CN102079760A - Method for synthesizing alpha-difluoro methylene phosphonic lactone - Google Patents
Method for synthesizing alpha-difluoro methylene phosphonic lactone Download PDFInfo
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Abstract
The invention discloses a method for synthesizing alpha-difluoro methylene phosphonic lactone. In the method, 2,3-allene phosphoni monoester substituted by alpha-difluoro methylene is used as raw material; an iodine cyclizing reagent is added into 2,3-allene phosphoni monoester; an intramolecular iodine cyclizing reaction is performed at normal temperature to obtain alpha-difluoro methylene phosphonic lactone with a six-membered ring structure. After being subjected to recrystallization or column chromatography purification, the prepared phosphonic lactone is expected to become an important enzyme inhibitor. The method is simple and convenient and has high efficiency, mild conditions and high yield. The yield of an aimed compound phosphonic lactone can reach 76 percent to 93 percent.
Description
Technical field
The present invention relates to the synthetic method of biologically active substance native annulus phosphoric acid ester analogue, particularly relate to the synthetic method of a kind of α-difluoro methylene phosphine lactone.
Background technology
Phosphoric acid ester is the very important organic substance of a class in the organism, plays a part key in the signal conductive process in biological cell, and is closely bound up with people's vital movement.Have two big kind phosphate esters in human body, a class is the phosphoric acid ester of open chain; An other class is the cyclic phosphoric acid ester.These phosphoric acid ester in vivo can with the plurality of enzymes combination, thereby bring into play various physiological effects.For example: the Triphosaden in the open chain phosphoric acid ester (ATP) is a significant energy carrier in the body, and uridine triphosphate participates in the synthetic of glycogen, and cytidine participates in the synthetic of phosphatide.And for example: cyclic amp in the cyclic phosphate (cAMP) and cyclic guanosine monophosphate (cGMP) be as the second messenger, play an important role in the signal conductive process in vivo (
Scheme 1)
ATP cAMP。
In recent years, the focus that the phosphoric acid ester material is studied mainly concentrates on and seeks the not analogue of the natural phosphoric acid ester of facile hydrolysis.These analogues are difficult for being discerned by enzyme in vivo, therefore can compete the action site of enzyme with natural phosphoric acid ester jointly; Because it is facile hydrolysis not, thereby can block some physiological effect that natural phosphoric acid ester produces.Research to natural phosphoric acid ester analogue is used to develop new enzyme inhibitors, explore natural phosphoric acid ester in vivo with the action site of enzyme, be used for setting forth intermolecular interaction process in the organism.
Though use P-CH
2It is design and a kind of important means of finding the natural phosphoric acid ester analogue of new not facile hydrolysis that-C key replaces the P-O-C in the natural phosphoric acid ester, but owing to CH in the phosphonic acid ester
2Electronegativity less than the electronegativity of O in phosphate-based, thereby the acidity that has directly caused phosphonic acid ester less than the parent phosphoric acid ester, therefore this phosphonate is successfully used to the living model aspect also exists very big restriction.
This problem is until just solved in 1981, and Blackburn found to work as O in the phosphoric acid ester dimer first by CF at that time
2After the replacement, because atomic radius that the F atom is less and high electronegativity, not only volume is suitable with the parent phosphoric acid ester to make so alternative gained phosphonic acid ester, what is more important is electrically suitable with the parent phosphoric acid ester, be the polar body (isopolar) such as grade of phosphoric acid ester, thereby be the analogue of very effective natural phosphoric acid ester.After this this conclusion has constantly obtained proof experimentally.From then on the natural phosphoric acid ester of facile hydrolysis has obtained using widely like the object space face difluoro methylene designing not as this strategy of bioisostere of oxygen.People design synthesized many contain the segmental natural phosphoric acid ester analogue of difluoro methylene phosphonic acid ester (
Scheme 2), study intravital signal conductive process as the potential enzyme inhibitors or as bioprobe.
Until so far, these natural phosphoric acid esters all are the fluorine-containing phosphonate ester compounds that concentrates on open chain like the research of thing, about the report of its synthetic method and biological activity aspect all a lot.And the research of the analogue of relevant annular phosphate α-difluoro methylene phosphine lactone still is in the blank stage at home and abroad.On the one hand the synthetic method of relevant this compounds report not almost has only several pieces of documents to relate to the synthetic of fluorine-containing phosphine lactone, and only as the by product of reaction or intermediate report (
Scheme 3).
On the other hand, owing to lack the synthetic method of this compounds, the relevant α-report of difluoro methylene phosphine lactone aspect biological activity has not yet to see all open documents.And biological intravital cyclic phosphate is except above-mentioned cAMP and cGMP with second messenger effect, also has the glucose ring phosphoric acid ester, 2 ', 3 '-cyclic phosphoric acid diester Nucleotide, riboflavin 4 ', 5 '-cyclic phosphoric acid diester, inositol 1,2-cyclic phosphate, C-LYSOPA, cyclic glycerophosphate or the like, as endogenic material, synthetic their analogue might be found efficiently, low toxicity, the medicine of specific effect is arranged.For example cAMP and cGMP and 1, all have in the 3-glyceryl alcohol cyclic phosphate phosphoric acid ester of six-membered cyclic structure (
Scheme 4).
The present invention synthesizes the analogue α-difluoro methylene phosphine lactone of the phosphoric acid ester of a series of six-membered cyclics closely around the problems referred to above by the iodine cyclization that joins alkene.
Summary of the invention
The object of the present invention is to provide a kind of method of synthetic α-difluoro methylene phosphine lactone of easy, efficient, mild condition.
The technical solution used in the present invention is as follows:
The synthetic method of a kind of α-difluoro methylene phosphine lactone, it is characterized in that: with 2 of α-difluoro methylene replacement, 3-connection alkenyl phosphonic acid monoesters is a raw material, adds the iodine cyclization reagent, normal temperature issues gives birth to intramolecular iodine cyclization, makes the α-difluoro methylene phosphine lactone with six-membered cyclic structure.
The inventive method is with 2 of α-difluoro methylene replacement, and 3-connection alkenyl phosphonic acid monoesters is a raw material, prepares the phosphine lactone of six-membered cyclic by intramolecular iodine cyclization.Described α-difluoro methylene phosphine lactone has structure shown in the following formula I:
Wherein become ring portion to be divided into monocycle or volution, substituent R
1Be H or alkyl, preferred H, C
1-C
5Alkyl; R
2Be H or alkyl, preferred H, C
1-C
5Alkyl; Perhaps R
1R
2Be connected to alkylidene group, preferred C
3-C
5Alkylidene group.
The synthetic α of institute-difluoro methylene phosphine lactone can be monocycle or spirane structure, for example the following compounds for preparing respectively among the embodiment:
Its reaction mechanism of the inventive method is that at first the iodine positive ion forms the iodide ion intermediate with connection alkene generation electrophilic addition reaction, and intramolecular then phosphono attack intermediate, highly selective obtain the product phosphine lactone of endo addition, and reaction process for example following formula is represented:
Ⅱ
Described α-difluoro methylene replaces 2, and 3-connection alkenyl phosphonic acid monoesters has suc as formula structure shown in the II R in the formula
1, R
2As previously mentioned.α-difluoro methylene replaces 2, and 3-connection alkenyl phosphonic acid monoesters can prepare by phosphonic acid diester ordinary-temp hydrolysis in NaOH solution, and the preparation of phosphonic acid diester can be referring to document (T. Yokomatsu, A. Ichimura, J. Kato, S. Shibuya, Synlett. 2 (2001) 287).
Described iodine cyclization reagent is I
2, N-iodo succimide (NIS) or ICl, preferred NIS.
Described iodine cyclization carries out in inert gas atmosphere.
The purifying of the inventive method synthetic phosphine lactone can adopt the method for recrystallization or column chromatography.
Because containing the phosphonic acid ester of α-difluoro methylene replacement is the bioisostere of natural phosphoric acid ester, the structural unit that all contains cyclic phosphate in the molecule of many biologically actives, linked reaction can further take place in the structure of the thiazolinyl iodine that is contained in the molecule in addition, this structure can be incorporated in other bioactive molecule, utilize present method synthetic phosphine lactone to be expected to become the important enzyme inhibitors of a class.
The inventive method be a kind of efficiently, the method for simply synthetic α-phosphine lactone that difluoro methylene replaces, this method is easy, mild condition, productive rate height, the yield of target compound phosphine lactone generally can reach 76%-93%.
Describe the present invention below in conjunction with specific embodiment.Protection scope of the present invention is not exceeded with embodiment, but is limited by claim.
Description of drawings
The single crystal X diffraction figure of the compound that Fig. 1 makes for embodiment 1.
Embodiment
Synthetic method according to α of the present invention-difluoro methylene phosphine lactone, with α with formula II structure-difluoro methylene replace 2,3-connection alkenyl phosphonic acid monoesters is a raw material, with the iodine cyclization reagent intramolecular iodine cyclization taking place at normal temperatures, makes the α-difluoro methylene phosphine lactone with six-membered cyclic structure.Described method is carried out in inert gas atmosphere usually, as at N
2Under the gas shiled, in reaction flask, add 2 of α-difluoro methylene replacement, 3-connection alkenyl phosphonic acid monoesters, iodine cyclization reagent (I
2, NIS or ICl) and solvent (as acetonitrile, methylene dichloride, acetonitrile/water), the mol ratio of connection alkenyl phosphonic acid monoesters and iodine cyclization reagent is 1:1.1-1:3, is reflected at normal temperature and carries out, (Thin Layer Chromatography TLC) follows the tracks of reaction to thin-layer chromatography; Reaction finishes back solubilizing agent dilution, washing, drying is filtered, after rotary evaporation removes and desolvates crude product phosphine lactone, crude product can adopt the method for recrystallization or column chromatography refining pure product.
Recrystallization can adopt the mixed solvent of non-polar solvent and polar solvent, as sherwood oil-methylene dichloride, and petroleum ether-ethyl acetate, normal hexane-ethyl acetate etc.Column chromatography can adopt silica gel as stationary phase, and developping agent is the mixed solvent of non-polar solvent and polar solvent, as sherwood oil-methylene dichloride, and petroleum ether-ethyl acetate, mixed solvents such as normal hexane-ethyl acetate.Its volume ratio of above-mentioned mixed solvent is non-polar solvent and polar solvent 2-7:1, as the mixed solvent of sherwood oil: ethyl acetate=3:1.
Embodiment 1
At N
2Under the gas shiled, in reaction flask, add 0.5 mmol 4,4-dimethyl-1,1-difluoro methylene-2,3-connection alkenyl phosphonic acid mono ethyl ester, 0.75 mmol NIS and 6 mL CH
3CN, normal-temperature reaction, TLC follows the tracks of, and adds the ethyl acetate dilution after reaction finishes, and uses 5% Na successively
2S
2O
3Solution and saturated common salt water washing, anhydrous sodium sulfate drying filters, and after rotary evaporation removed and desolvates, crude product got pure product with rapid column chromatography.
Resulting its structure of phosphine lactone is as shown in the formula, yield 88%.
m.p.:?90-91?°C.
IR?(KBr):?1623,?1268,?1046,?1005?cm
-1.
1H?NMR?(300?MHz,?CDCl
3):?δ?6.56-6.45?(m,?1?H),?4.36-4.26?(m,?2?H),?1.75?(s,?3?H),?1.69?(s,?3?H),?1.36?(t,?
J?=?6.9?Hz,?3?H).
13C?NMR?(100?MHz,?CDCl
3):?δ?132.6-131.9?(m),?116.3-116.1(m),?108.6?(td,?
J C-F?=?254.0?Hz,?
J C-P?=?200.0?Hz),?89.4?(d,?
J C-P?=?8.0?Hz),?65.6?(d,?
J C-P?=?6.0?Hz),?29.7,?29.4,?16.3?(d,?
J C-P?=?5.2?Hz).
19F?NMR?(282?MHz,?CDCl
3):?δ?-104.51?(ABdd,?
J F-F?=?316.6?Hz,?
J P-F?=?92.8?Hz,
?J H-F?=?10.7,?9.0,?8.2,?7.6,?7.3?Hz).
31P?NMR?(121?MHz,?CDCl
3):?δ?1.07?-?-0.12?(m).
EIMS?
m/z?(%):?353?(M
++1,?4.78),?244?(34.00),?197?(9.18),?117?(100.00),?97?(52.12),?77?(29.19),?65?(8.49),?51?(11.43),?43?(9.14).
Anal.?Calcd?for?C
8H
12F
2IO
3P:?C,?27.29;?H,?3.44.?Found:?C,?27.31;?H,?3.43。
Embodiment 2
At N
2Under the gas shiled, in reaction flask, add 0.5 mmol 4-(tetramethylene)-1,1-difluoro methylene-2,3-connection alkenyl phosphonic acid mono ethyl ester, 0.75 mmol NIS and 6 mL CH
3CN, normal-temperature reaction, TLC follows the tracks of, and adds the ethyl acetate dilution after reaction finishes, and uses 5% Na successively
2S
2O
3Solution and saturated common salt water washing, anhydrous sodium sulfate drying filters, and after rotary evaporation removed and desolvates, crude product got pure product with rapid column chromatography.
Resulting its structure of phosphine lactone as shown in the formula,
m.p.:?101-102?°C.
IR?(KBr):?1619,?1287,?1044,?1000?cm
-1.
1H?NMR?(300?MHz,?CDCl
3):?δ?6.69-6.57?(m,?1?H),?4.41-4.31?(m,?2?H),?2.40-2.33?(m,?3?H),?2.19-2.11?(m,?1?H),?2.00-1.72?(m,?4?H),?1.42?(t,?
J?=?6.9?Hz,?3?H).
13C?NMR?(125?MHz,?CDCl
3):?δ?133.9-133.4?(m),?116.4-116.2?(m),?109.5?(td,?
J C-F?=?255.2?Hz,?
J C-P?=?200.5?Hz),?98.9?(d,?
J C-P?=?8.8?Hz),?65.7?(d,?
J C-P?=?6.1?Hz),?41.1,?40.6,?24.3,?24.2,?16.4?(d,?
J C-P?=?5.0?Hz).
19F?NMR?(282?MHz,?CDCl
3):?δ?-103.34?(ABdd,?
J F-F?=?318.1?Hz,?
J P-F?=?94.0?Hz,
?J H-F?=?9.6,?8.7,?8.2,?7.3?Hz).
31P?NMR?(121?MHz,?CDCl
3):?δ?-1.47?-?-3.29?(m).
EIMS?
m/z?(%):?378?(M
+,?1.96),?270?(51.69),?203?(27.17),?143?(100),?101?(36.62),?91?(31.29),?79?(58.06),?77?(48.18).
Anal.?Calcd?for?C
10H
14F
2IO
3P:?C,?31.77;?H,?3.73.?Found:?C,?31.61;?H,?3.86。
Embodiment 3
At N
2Under the gas shiled, in reaction flask, add 0.5 mmol 4,4-diethyl-1,1-difluoro methylene-2,3-connection alkenyl phosphonic acid mono ethyl ester, 1 mmol I
2With 6 mL CH
3CN, normal-temperature reaction, TLC follows the tracks of, and adds the ethyl acetate dilution after reaction finishes, and uses 5% Na successively
2S
2O
3Solution and saturated common salt water washing, anhydrous sodium sulfate drying filters, and after rotary evaporation removed and desolvates, crude product got pure product with rapid column chromatography.
Resulting its structure of phosphine lactone as shown in the formula,
m.p.:?39-40?°C.
IR?(KBr):?1619,?1285,?1053,?1001?cm
-1.
1H?NMR?(300?MHz,?CDCl
3):?δ?6.76-6.64?(m,?1?H),?4.39-4.31(m,?2?H),?2.11-1.94?(m,?4?H),?1.41?(t,?
J?=?6.9?Hz,?3?H),?1.02?(t,?
J?=7.2?Hz,?3?H),?0.96?(t,?
J?=7.2?Hz,?3?H).
13C?NMR?(CDCl
3,?125?MHz):?δ?134.6-134.1?(m),?115.2-115.0?(m),?110.0?(td,?
J C-F?=?253.7?Hz,?
J C-P?=?199.1?Hz),?94.5?(d,?
J C-P?=?9.8?Hz),?65.6?(d,?
J C-P?=?6.0?Hz),?32.0,?31.7,?16.3?(d,?
J C-P?=?5.1?Hz),?7.2,?7.0.
19F?NMR?(282?MHz,?CDCl
3):?δ?-102.21?(ABdd,?
J F-F? =?318?Hz,?
J P-F?=?93?Hz,
?J H-F?=?10.1,?9.3,?8.7,?7.3?Hz).
31P?NMR?(121?MHz,?CDCl
3):?δ?-1.51?-?-3.02?(m).
EIMS?
m/z?(%):?380?(M
+,?63.06),?331?(48.38),?303?(100.00),?233?(50.65),?145?(41.77),?125?(37.70),?77?(42.07),?65?(30.71).
Anal.?Calcd?for?C
10H
16F
2IO
3P:?C,?31.60;?H,?4.24.?Found:?C,?31.77;?H,?4.28。
Claims (10)
1. the synthetic method of α-difluoro methylene phosphine lactone, it is characterized in that: with 2 of α-difluoro methylene replacement, 3-connection alkenyl phosphonic acid monoesters is a raw material, adds the iodine cyclization reagent, normal temperature issues gives birth to intramolecular iodine cyclization, makes the α-difluoro methylene phosphine lactone with six-membered cyclic structure.
2. the synthetic method of α according to claim 1-difluoro methylene phosphine lactone is characterized in that: described α-difluoro methylene phosphine lactone has structure shown in the following formula I:
I is substituent R wherein
1Be H or alkyl, R
2Be H or alkyl; Perhaps R
1R
2Be connected to alkylidene group.
3. the synthetic method of α according to claim 2-difluoro methylene phosphine lactone is characterized in that: described substituent R
1Be H or C
1-C
5Alkyl, R
2Be H or C
1-C
5Alkyl; Perhaps R
1R
2Be connected to C
3-C
5Alkylidene group.
4. the synthetic method of α according to claim 1-difluoro methylene phosphine lactone is characterized in that: described α-difluoro methylene replaces 2, and 3-connection alkenyl phosphonic acid monoesters has suc as formula structure shown in the II,
Substituent R in the formula
1Be H or alkyl, R
2Be H or alkyl; Perhaps R
1R
2Be connected to alkylidene group.
5. the synthetic method of α according to claim 1-difluoro methylene phosphine lactone is characterized in that: described iodine cyclization reagent is I
2, N-iodo succimide or ICl.
6. the synthetic method of α according to claim 5-difluoro methylene phosphine lactone is characterized in that: described iodine cyclization reagent is a N-iodo succimide.
7. the synthetic method of α according to claim 1-difluoro methylene phosphine lactone is characterized in that: 2 of described α-difluoro methylene replacement, the mol ratio of 3-connection alkenyl phosphonic acid monoesters and iodine cyclization reagent is 1:1.1-1:3.
8. the synthetic method of α according to claim 1-difluoro methylene phosphine lactone is characterized in that: described iodine cyclization carries out in acetonitrile, methylene dichloride or acetonitrile/water mixed solvent.
9. the synthetic method of α according to claim 1-difluoro methylene phosphine lactone is characterized in that: described iodine cyclization carries out in inert gas atmosphere.
10. the synthetic method of α according to claim 1-difluoro methylene phosphine lactone is characterized in that: the α that the iodine cyclization makes-difluoro methylene phosphine lactone adopts the method for recrystallization or column chromatography to carry out purifying.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105418685A (en) * | 2015-11-11 | 2016-03-23 | 南京师范大学 | Synthetic method for six-membered cyclic difluoromethylene phosphine lactone |
Citations (1)
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| CN1036578A (en) * | 1988-04-01 | 1989-10-25 | 米勒陶氏药物公司 | Novel fluorophosphonate nucleotide derivatives |
-
2010
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1036578A (en) * | 1988-04-01 | 1989-10-25 | 米勒陶氏药物公司 | Novel fluorophosphonate nucleotide derivatives |
Non-Patent Citations (4)
| Title |
|---|
| 《Chinese Chemical Letters》 20070123 Yun Lin et al. Convenient synthesis of beta-allenic alpha-difluoromethylenephosphonic acid monoesters: Potential synthons for cyclic phosphate mimics 1-10 第18卷, 第1期 * |
| 《Tetrahedron Letters》 20060713 Yun Lin et al. First iodocyclization of beta-allenic phosphonates: a novel synthesis of alpha-difluoromethylenephostones 1-10 第47卷, 第34期 * |
| YUN LIN ET AL.: "Convenient synthesis of β-allenic α-difluoromethylenephosphonic acid monoesters: Potential synthons for cyclic phosphate mimics", 《CHINESE CHEMICAL LETTERS》, vol. 18, no. 1, 23 January 2007 (2007-01-23), XP005943270, DOI: doi:10.1016/j.cclet.2006.11.029 * |
| YUN LIN ET AL.: "First iodocyclization of β-allenic phosphonates: a novel synthesis of α-difluoromethylenephostones", 《TETRAHEDRON LETTERS》, vol. 47, no. 34, 13 July 2006 (2006-07-13) * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105418685A (en) * | 2015-11-11 | 2016-03-23 | 南京师范大学 | Synthetic method for six-membered cyclic difluoromethylene phosphine lactone |
| CN105418685B (en) * | 2015-11-11 | 2017-07-28 | 南京师范大学 | A kind of synthetic method of six-membered cyclic difluoro methylene phosphonic lactone |
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