JPH0530837B2 - - Google Patents

Description

[Detailed description of the invention]

(Field of Industrial Application) The present invention relates to a method for synthesizing various phosphosaccharide derivatives that are expected to have physiological activity in the pharmaceutical field. (Prior Art) Phosphorus sugar is a phosphorus derivative of sugar, particularly a compound having a phosphorus atom in the hemiacetal ring of sugar.
Amino sugars and thiosaccharides, which are heteroatom derivatives of sugars other than phosphorus, exist in nature as natural products, and are compounds with physiological activities such as antibiotics and blood sugar concentration increasing effects. Although little is known about the physiological effects of phosphosaccharide, (-)-(1R,2S)-1,2-epoxypropylphosphonic acid, a natural product with a C-P bond, is an antibiotic with antiviral activity. Cyclophosphamide, a phosphorus-containing cyclic compound, is an important antitumor drug, and it is also known that 5-deoxy-1,5-C-(ethylphosphinylidene)-β-D-glucose derivatives It can be inferred from the fact that it exhibits a weak but anticancer effect.
Phosphorous sugar is expected to have important physiological effects such as anti-cancer and anti-AIDS effects. The conventional phosphorus sugar synthesis method uses sugar as a starting material, converts the hydroxyl group into a functional group and introduces a protective group to functionalize only the necessary reaction sites, and then converts the sugar backbone into a sugar skeleton by reaction with a phosphorus compound. The method involved introducing a carbon-phosphorus bond into the hemiacetal ring, followed by functional group conversion on the phosphorus atom and hydrolysis of the hemiacetal ring to introduce the phosphorus atom into the hemiacetal ring. A typical example is shown by the following series of reactions. These conventional methods have the following problems: (1) Large-scale synthesis is difficult due to the long reaction route; (2) Since sugar is used as a starting material, the starting materials that can be used are severely limited from an economic standpoint; (3) The types of phosphorus sugars that can be synthesized are limited. (4) Phosphorus reactions and functional group conversion reactions of phosphorus compounds are often accompanied by great difficulties and yields are low. (5) Reactions using ozonolysis require short reaction times. There were problems such as the fact that if the reaction time is too long, side reactions will proceed, making it difficult to scale up the reaction, and (6) there are difficulties in industrializing it from an economic and process standpoint. Therefore, there have been few cases where phosphosaccharide has been synthesized, and the yield of the compound has been extremely small, so although it is expected to be an important physiologically active substance, only extremely limited activity tests have been conducted. Currently, the development of uses such as pharmaceuticals is left to future results. (Problems to be Solved by the Invention) The present invention was completed as a result of research from a completely different approach from the conventional method in order to solve the various problems associated with the above-mentioned conventional method. Breaking away from the past fixed idea that ``sugar derivatives are synthesized starting from sugar,'' this method is based on a shift in the idea of ``synthesizing sugar derivatives from compounds other than sugar.'' That is, the object of the present invention is to provide a method for efficiently and economically synthesizing many types of phosphosaccharides from a wide variety of inexpensive starting materials through simplified steps, which can be mass-produced on a commercial scale. is to provide. (Means for solving the problem) The above purpose is to perform an addition reaction with a conjugated diene or tri-halogenated phosphorus compound to form a compound of the general formula () [However, R ¹ is a hydrogen atom, a hydroxyl group, an alkyl group,
Alkoxyl group, aryl group, or aryloxyl group; R ² and R ³ are each a hydrogen atom, alkyl group, alkoxyl group, or aryl group; R ⁴ is a hydrogen atom, hydroxyl group, alkyl group, alkoxyl group, aryl group, acyloxyl group, or aryl group; royloxyl group; and R ⁵ each represent a hydrogen atom, a C ₁₂ alkyl group, a hydroxymethyl group, a hydroxyethyl group, a dihydroxyethyl group, or an acyl derivative thereof. The ethylene bond of the phosphorene oxide is saturated by an addition reaction of hydroxyl groups by oxidation of an alkali metal or alkaline earth metal chlorate in the presence of a catalytic amount of osmium tetroxide. So, the general formula () [However, R ¹ to ^{R 5} are the same as above] This is achieved by a method for synthesizing a phosphorus sugar derivative, which is characterized by converting it into a phosphorane compound represented by the following. The configuration of the present invention will be explained in further detail below. In the first step of the method of the present invention, the phosphorene oxide of the general formula () is easily obtained by treating the adduct resulting from the reaction of a conjugated diene with a di- or trihalogenated phosphorus compound with water or alcohol. obtain. For example, the following conjugated dienes are particularly suitable, but the diene is not limited thereto as long as a phosphorene compound can be produced by addition of a di- or trihalogenated phosphorus compound. 1,3-butadiene, 2-methyl-1,3-butadiene (isoprene), 2-phenyl-1,3-butadiene, 2-hydroxy-1,3-butadiene, 1-methoxyl-2-methyl-butadiene, 2 -methoxyl-1,3-butadiene, 3-hydroxy-1,3-pentadiene, 5-hydroxy-1,3-pentadiene, 5-acetoxy-1,3-pentadiene, 5-benzoyloxy-1,3-pentadiene, 1,3-hexadiene, 1,3-hexadiene-5,6-diol, 5-hydroxy-6-acetoxy-1,3-hexadiene, 5-hydroxy-6-benzoyloxy-1,
3-hexadiene, etc. Further, the di- or trihalogenated phosphorus compound added to these conjugated dienes is a phosphine represented by the following formula PR ¹ X ₂ or PX ₃ , where R ¹ is a hydrogen atom,
It is selected from a hydroxyl group, an alkyl group or an alkoxyl group (preferably one having 1 to 8 carbon atoms), an aryl group or an aryloxyl group (preferably a phenyl group or a phenoxy group), and X is a halogen atom, preferably chlorine. In the phosphorene oxide of the above formula () derived from an adduct of a conjugated diene and a di- or trihalogenated phosphorus compound, R ¹ , R ² , R ³ ,
R ⁴ and R ⁵ each represent the following atoms or atomic groups. R ¹ : hydrogen atom, hydroxyl group, alkyl group or alkoxyl group (preferably one having 1 to 8 carbon atoms), aryl group or aryloxyl group (preferably phenyl group, phenoxy group); R ² , R ³ : hydrogen atom, Alkyl group (preferably methyl group) and aryl group (preferably phenyl group); R ⁴ : hydrogen atom, hydroxyl group, alkyl group or alkoxyl group (preferably methyl group, methoxyl group), aryl group (preferably phenyl group), Acyloxyl group (preferably acetoxyl group, and aryloyloxyl group (preferably benzoyloxyl group); R ⁵ : hydrogen atom, methyl group, hydroxymethyl group or their acyl derivative group (especially acetoxymethyl group, benzoyloxymethyl group) ), and ethyl, hydroxyethyl, dihydroxyethyl groups or their acyl derivatives (especially ethylene glycolyl, α-acetoxy-
β-hydroxy-ethyl group, α-benzoyloxy-β-hydroxy-ethyl group, α-hydroxy-β-acetoxy-ethyl group, α-hydroxy-β-benzoyloxy-ethyl group, α,
β-diacetoxyethyl group, and α,β-dibenzoyloxy-ethyl group). In the second step following the first step of the method of the present invention, using phosphorene oxide represented by the formula () as a starting material, the endocyclic ethylene bond is preferably removed by an addition reaction of a hydroxyl group by oxidation. Converts saturated phosphorane oxide into phosphorus sugar as its basic skeleton. The reaction is expressed by the following equation. (However, R ¹ to ^{R 5} are the same as above.) Oxidation is usually performed using potassium chlorate, sodium chlorate, chlorine, etc. in an aqueous solvent such as a water-miscible organic solvent such as tetrahydrofuran in the presence of a catalytic amount of osmium tetroxide. This can be smoothly carried out by applying an alkali metal salt or alkaline earth metal salt of chloric acid, such as barium acid, to the reaction at a temperature below the boiling point of the organic solvent while stirring. In addition, as an oxidizing agent, peroxides such as hydrogen peroxide or other known and commonly used oxidizing agents can be used as appropriate in place of the above-mentioned chlorate, and by changing the oxidizing agent, the three-dimensional structure of the phosphorus sugar produced can be changed. be able to. After completion of the reaction, the phosphorane oxide product represented by the above formula () is isolated with a high yield of over 90% through conventional separation operations such as distillation of the solvent under reduced pressure and extraction with chloroform. It will be done. As mentioned above, in order to further chemically modify the target phosphosaccharide synthesized by the method of the present invention, the hydroxyl group of the glycero group is blocked to identify the reactive group in the phosphoric acid moiety. The need arises. Blocking of hydroxyl groups is usually carried out by acetylation using acetic anhydride in a pyridine solvent. The reaction is shown in the following formula. Further, if acetone is treated in the presence of copper sulfate under acidic conditions, it can be converted into didehydro as shown in the following formula, and in this case, it is also possible to deblock it if necessary. Furthermore, blocking can also be achieved by epoxidizing the ethylene bond of phosphorene oxide. Examples of the phosphorus sugar and its derivatives obtained through the method of the present invention include the following. (a) 3-deoxy-1,4-(phenylphosphinylidene)-α-D-glycerotetraose, (b) 3-deoxy-1,4-(phenylphosphinylidene)-α-L- Glycerotetraose, (c) 3-deoxy-1,4-(hydroxyphosphinylidene)-α-D-glycerotetraose, (d) 3-deoxy-1,4-(hydroxyphosphinylidene)-α- L-glycerotetraose, (e) 3-deoxy-1,4-(alkylphosphenylidene)-α-D-glycerotetraose, (f) 3-deoxy-1,4-(alkylphosphenylidene)- α-L-glycerotetraose, (t)3-deoxy-2-methyl-1,4-(phenylphosphinylidene)-α-D-glycerotetraose, (th)3-deoxy-2-methyl- 1,4-(phenylphosphinylidene)-α-L-glycerotetraose, (li)3-deoxy-2-methyl-1,4-(phenylphosphinylidene)-α-D-glycerotetraose , (nu) 3-deoxy-2-methyl-1,4-(phenylphosphinylidene)-α-L-glycerotetraose, (l) β-D and β-L of (i) to (f) α- of hydroxyphosphinylidene and alkylphosphinylidene derivatives of (w) (g) and (h)
D, α-L, α-D, α-L forms, (W) All erythrose and threose derivatives corresponding to the 3-hydroxyl forms of (A) to (W), (F) Pentoses (arabinose, ribose, (y) All phosphosaccharides corresponding to hexoses (glucose, mannose, allose, altrose, talose, galactose, idose, gyulose, etc.); (t) All phosphosaccharides corresponding to the above (i) ) - All derivatives such as acetyl compounds obtained from (y). (Operation) Phosphorene oxide, which is the target substance in the first step of the method of the present invention, can be easily obtained by the reaction of a diene having a highly reactive conjugated double bond with a phosphine having a halogen atom, which also has a high activity. The phosphorene oxide can be easily obtained by treating the adduct with water or alcohol, and the ethylene bond in the ring can be easily saturated in a single step of oxidation under mild conditions in the second step. It is converted into phosphorus sugar or deoxyhalophosphorus sugar with high yield. The three-dimensional structures of these phosphosaccharides can be made different by appropriately changing the oxidizing agent. Furthermore, the phosphosaccharide obtained by the method of the present invention can be made into a wide variety of phosphosaccharide derivatives by blocking unnecessary functional groups as necessary and performing various chemical modifications. If so, it is possible to deblock it. (Example) Hereinafter, the present invention will be further explained with reference to Examples.
In the examples, % represents weight percent based on the theoretical yield. Example 1 Synthesis of 3-deoxy-2-C-methyl-1,4-(phenylphosphinylidene)-α-L-glycerotetraose 3-Methyl-1-phenyl-2-phosphorene oside (yield
54%, MS (m/e) = 192 (M ⁺ ), structure confirmed by IR and NMR spectra) 2.89 g (15.1 mmol) of water
A solution of 33 ml and 17 ml of tetrahydrofuran was placed in an eggplant-shaped flask and kept at 45-50°C. Catalytic amounts of osmium tetroxide 0.1g and potassium chlorate 2.63g
(21.5 mmol) and reacted with stirring for 18 hours. After the reaction was completed, the solvent was distilled off under reduced pressure, and the residue was extracted with chloroform. After filtering off the insoluble matter and drying the filtrate, the solvent was distilled off to give 3-deoxy-1,4-(phenylphosphinylidene)-
α-L-glycerotetraose 2.64g (yield 91
%) was obtained. It was recrystallized from carbon tetrachloride. mp:
It was 185-188°C, [α] ¹⁶ _D : +3.5°. MS, IR,
The structure was confirmed by ¹ H-NMR and elemental analysis. Example 2 Synthesis of 3-deoxy-1-C-methyl-1,4-(phenylphosphinylidene)-α-L-glycerotetraose Addition reaction between 1,3-pentadiene and dichlorophenylphosphine and , 3-deoxy-1-C-methyl-1,4 was obtained in the same manner as in Example 1 from 2-methyl-1-phenyl-2-phosphorene oxide obtained by subsequent treatment with water.
-(Phenylphosphinylidene)-α-L-glycerotetraose was synthesized. Example 3 Synthesis of 3-deoxy-2-C-methyl-1,4-(methoxyphosphinylidene)-α-L-glycerotetraose Obtained by addition reaction of isoprene with phosphorus trichloride and subsequent treatment with methanol. From the obtained 3-methyl-1-methoxy-2-phosphorene oxide, 3-deoxy-2-C-methyl-1,4-(methoxyosphinylidene)- α-L-glycerotetraose was synthesized. Example 4 Synthesis of 3-deoxy-1,4-(methoxyphosphinylidene)-α-L-glycerotetraose Obtained by addition reaction of 1,3-butadiene and phosphorus trichloride and subsequent treatment with methanol From 1-methoxy-2-phosphorene oxide,
In the same manner as in Example 1, 3-deoxy-
1,4-(methoxyphosphinylidene)-α-L-
Glycerotetraose was synthesized. Example 5 3-deoxy-1-C-methoxy-2-C-methyl-1,4-(phenylphosphinylidene)-
Synthesis of α-L glycerotetraose 1-phenyl-2-methoxy-3 obtained by addition reaction of 1-methoxy-2-methyl-1,3-butadiene and dichlorophenylphosphine and subsequent treatment with water -From methyl-2-phosphorene oxide, in the same manner as in Example 1,
3-deoxy-1-C-methoxy-2-C-methyl-1,4-(phenylphosphinylidene)-α-
L-glycerotetraose was synthesized. Reference Example 1 Synthesis of 3-deoxy-1,2-O-isopropylidene-2-C-methyl-1,4-(phenylphosphinylidene)-α-L-glycerotetraose 3-deoxy-2-C obtained in Example 1 above
-Methyl-1,4-(phenylphosphinylidene)
-α-L-glycerotetraose 0.90g (4.0m
mol), 16 ml of dry acetone, 1.59 g of anhydrous copper sulfate,
0.08 ml of concentrated sulfuric acid was added, and the mixture was allowed to react at room temperature for 24 to 48 hours with stirring. The reaction mixture was neutralized with calcium hydroxide, the solid matter was filtered off, the acetone was distilled off under reduced pressure, the residue was extracted with chloroform, and the chloroform was further distilled off under reduced pressure to obtain 3-deoxy-1, 2
-O-isopropylidene-2-C-methyl-1,
1.06 g (yield: 100%) of 4-(phenylphosphinylidene)-α-L-glycerotetraose was obtained.
The structure was confirmed by MS, IR, and ¹ H-NMR. Reference example 2 3-deoxy-1,2-epoxy-2-C-methyl-1,4-(phenylphosphinylidene)-
Synthesis of α-L glycerotetraose The 3-methyl-1-phenyl-2-phosphorene oxide solution used as the starting material in Example 1 was treated with a stoichiometric amount of trifluoroperacetic acid, and the ethylene bond was Add one oxygen atom and perform epoxidation to synthesize 3-deoxy-1,2-epoxy-2-C-methyl-1,4-(phenylphosphinylidene)-α-L-glycerotetraose did. Reference example 3 3-deoxy-1,2-di-0-acetyl-
1,4-(phenylphosphinylidene)-α-L
-Synthesis of glycerotetraose 3-deoxy-1,4 obtained in Example 5
-(Methoxyphosphinylidene)-α-L-glycerotetraose was treated with acetic anhydride in a pyridine solvent, and 3-deoxy-1,2-di-0-acetyl-1,4-(phenylphosphinylidene) )−α−
L-glycerotetraose was synthesized. The yield, MS (m/e), IR (cm
^-1 ), [α] _D The chemical structures confirmed with reference to each measured value, ¹ H-NMR and elemental analysis results are shown in the following table.

【table】

【table】

[Table] (Effects of the invention) The starting materials to which the method of the present invention is applied are dienes,
In particular, since it uses compounds such as butadiene and isoprene, which are widely used in various chemical industries including rubber synthesis, as raw materials, it is inexpensive, and various derivatives can be easily obtained in large quantities, making it possible to produce an extremely wide variety of phosphorus products. Sugar can be synthesized in large quantities at low cost. In addition, the synthesis route is extremely short and the reaction conditions are mild, so the reaction operation and equipment are simple.
It is an extremely advantageous and suitable method from the economic and industrial viewpoints, such as the ability to obtain a highly purified target product with a high yield. Furthermore, it is easy to synthesize derivatives of starting materials and chemically modify phosphorus sugars;
The advantage of being able to synthesize multiple products, combined with the advantage of mass production, makes it easy to verify the use of various phosphosaccharides as pharmaceuticals, which makes it possible to develop new uses as new physiologically active substances, especially as anticancer drugs. There are great expectations for the search for anti-AIDS drug sugars.

Claims (1)

[Scope of Claims] 1 Addition reaction of a di- or tri-halogenated phosphorus compound to a conjugated diene results in the formation of the general formula () However, R ¹ is a hydrogen atom, a hydroxyl group, an alkyl group,
Alkoxyl group, aryl group, or aryloxyl group; R ² and R ³ are each a hydrogen atom, alkyl group, alkoxyl group, or aryl group; R ⁴ is a hydrogen atom, hydroxyl group, alkyl group, alkoxyl group, aryl group, acyloxyl group, or aryl group; royloxyl group; and R ⁵ each represent a hydrogen atom, a C _1-2 alkyl group, a hydroxymethyl group, a hydroxyethyl group, a dihydroxyethyl group, or an acyl derivative thereof. The ethylene bond of the phosphorene oxide is saturated by an addition reaction of hydroxyl groups by oxidation of an alkali metal or alkaline earth metal chlorate in the presence of a catalytic amount of osmium tetroxide. So, the general formula () [However, R ¹ to ^{R 5} are the same as above] A method for synthesizing a phosphorus sugar derivative, which comprises converting it into a phosphorane compound represented by the following.