TWI324931B - Process for preparation of cyclic prodrugs of pmea and pmpa - Google Patents

Description

Nine, the invention description: [Technical field to which the invention belongs] R 9 : f Ϊ i (2_麟卿oxyethyl) adenine (·Α) and 4:5 A; ff base 呤 (ΡΜΡΑ) Has the ability to be replaced, the financial 1 synthesis step. More precisely, the γ 1 (2 鳞 methoxyethyl) adenine and R-9- (2 phosphine terracotta) gland σ 呤 具有 have been replaced by a halogen group A cyclic 丨-phenyl-ij-propane ester having a forward stereochemical structure. [Prior Art] The prior art described below is provided to assist in the understanding of the present invention, but does not endorse or express all publications of the present invention as a complete reference. 9-(2-phosphonium-decyloxyethyl)adenine (PMEA), (8)_9_(2·lin-methoxypropyl)adenine (PMPA) and phase analogs (US Patent No. 4,808,716; US Patent No. 5, 142, 0510) are phosphates with antiviral activity 'including anti-hepatitis B and human AIDS virus (De Ciercq et vomit, Antiviral Res. 8: 261-7 (1987); Balzarini et al., Biochem

Biophys. Res. Commun. 219(2): 337-41 (1996)). Dipivaloyloxymethyl ester of 9-(2-phosphoniumoxyethyl)adenine (BisPOMPMEA) is a clinically used drug for the treatment of hepatitis B (Benhamou et al., Lanccet 358 (9283): 718-23 ( 2001)). In addition, some studies have shown that such compounds also have anti-cancer activity (Murono et al., Cancer Res. 61 (21): 7875-7 (2001). 1324931 contains phosphonic acids Compounds and their salts have high acidity values under physiological conditions in humans, so oral administration of such drugs is generally low in bioabsorbability, low in cell permeability and can only be distributed to certain tissues (eg central nervous system). In addition, these acids also contain other properties that prevent their development into drug use, including low plasma half-life and toxicity problems (such as kidney and gastrointestinal tract) due to their high clearance rate in the kidneys (Bijsterbosch et Al., Antimicrob Agents Chemother. 42(5): 1146-50 (1998). Cyclic phosphonates are also used to describe 9-(2-phosphoniumoxyethyl)adenine and its analogs. This type of cyclic phosphonic acid vinegar is shown below

The L3-propanoid which is not substituted in the ring of the 9-(2-phosphonium methoxyethyl) adenine compound was synthesized and tested in vivo to be inactive and inactive. The position of the 1,3 position of the cyclic drug precursor of 9-(2-phosphonooxyethyl)adenine is not substituted in the European Patent No. EP0481214B1. The application of this inventor (Starrett et al) J. Med. Chem. 37: 1857-1864 (1994) and the publication of subsequent articles further reveal that the compound they found is not orally bioavailable and biologically inactive. This compound is unstable at low acidity. As the study shows, the cyclic 2,2,-difluoro-1,3,-propane ester is easily hydrolyzed and unstable to form a ring-opened monomer structure. SUMMARY OF THE INVENTION The present invention discloses a novel and enhanced diastereoisomer (de) excess of the amount of the cis isomer to synthesize 9-(2-phosphonium methoxyethyl) adenine呤 and R-9-(2-phosphonium methoxypropyl) adenine ring: _ arene group], 3-propenylphosphonic acid cyclic ester synthesis step. In the synthesis process of the present invention by coupling The method of (coupling method) increases the anisomer. On the other hand, the amount of the isomer is increased by the temperature change during the synthesis, and the isomer is also made by the order of the reactants being added. The increase in yield is further enhanced by the increase in the amount of acid and crystalline salts added. The production of isomers is increased. On the other hand, the use of a crystallization solvent also increases the amount of isomers during the synthesis. On the other hand, the present invention discloses a method for producing a pure cis with a chemical steric structure attached to its S. The present invention discloses a process for preparing the compound. The structure of the compound is as shown in Chemical Formula I:

In the formula I, the molecular formula is protected from each other by a gland, which is composed of a gland containing 9 (2 醯 子-ethoxyethyl) adenine and a ruthenium -9 unicorn-methoxypropyl) The phosphonic acid selected in the sputum; and V refers to the phenyl group, arbitrarily replacing 12 molecules of fluorine, chlorine, and desert groups; including a pair of shirts, 1324391, C-1,3-1 The phenyl group of the alcohol can be optionally substituted with a mp〇ci2 or N-6 substituted analog. Additionally, the methods and salts disclosed herein can be used to extract and purify the desired isomers. DEFINITIONS Unless otherwise stated, the specific nouns used in the present invention will be defined in the following description. "Positively burned" refers to a solution currently available on the market for high performance liquid chromatography, which consists of 95% n-hexane, methylcyclopropane and decylpentane. "Dialkyl" means that there are two alkyl groups in the compound. As used herein, a base of a saturated aliphatic group includes a straight chain, a branched chain, and a cyclic group. Saturated alkyl groups include mercapto, ethyl, isopropyl and cyclopropyl. "Arbitrarily substituted, or,, replaced, includes an alkyl group substituted with one or two substituents (substituents) selected from the group consisting of a lower alkyl group, a lower aromatic hydrocarbon group, and a halogen group. The substituent group is more usually a halogen group. The forward chemical stereo structure refers to the positional relationship between the V group and the μ group on the six composition chains. The following chemical formula represents the forward chemical stereo structure.

V

The position of the other forward chemical solid structure V*M is the same as above the plane. The chemical formula is shown in the figure below. 10 1324931

"N6-substituted" means that an amine is added to the position of six carbons in the anthracene ring. N6_ is usually substituted with a dialkylamine methylene group, and the position at R1 is usually, but not limited to, an acyclic alkyl group of one to four carbons, a cyclic alkyl group of five to six carbons, and a methyl group. The phenethyl group or the R1 group together form a hexahydro 1»piperdine, a 1,4-oxo morphineeine, and a η ratio bite.

"A monoalkylamino vinylimine" refers to a functional group or a structure substituted as follows:

The R group may be, but not limited to, an acyclic alkyl group having one to four carbons, a cyclic alkyl group having five to six carbons, a phenyl group, a phenethyl group or an R1 group having a hexahydro group, 1.4. Oxygen and nitrogen land mites and the form of transfer coexist.

The program calculates that:

EIiiIS] X 100-〇/〇R.〇/〇S

[R] + [S]

丄J • [R] refers to the number of R isomers, and [S] refers to the number of s = isomers. This equation calculates the percentage of mirror image isomers when the R isomer is predominant. The term "d.e." as used herein refers to an amount in which the diastereomer exceeds. It can be calculated from the following equation:

[Tear]+ [and life I

"Diastereomer" refers to a chemical reaction in which two or more asymmetric centers of the compound have the same substituent and undergo the same form of chemical reaction. The diastereomers have different physiological properties. The substitution group is present in a relatively different orientation lang, and may be the same as the biosynthesis Z "racemic property", which refers to a compound or mixture of optically active ability consisting of the same amount of right-handed and left-handed rotations of the same compound. "Mirror image isomer" means that the molecular structure of a chemical compound has a mirror image relationship with each other. "Acid decomposition coefficient, (Ka) refers to the equilibrium coefficient of acid ionization, for example, HA refers to a weak acid. then:

Ka = ([H+][A]/[HA]) Halogen" refers to chlorine, desert or fluorine. "Pharmaceutical precursor" means in the present invention any M compound is added to the biological system via individual or mutual spontaneous Sexual chemical reactions, enzyme-catalyzed chemical reactions, and/or metabolic chemical reactions produce compounds that are biologically active. A standard drug precursor consists of a group of drugs that can be cleaved in vivo, such as HO-, HS-, HOOC-, R2N_. Standard drug precursors include, but are not limited to, carboxylate esters, wherein the group is alkyl, aryl, aralkyl, decyloxyalkyl, alkoxycarbonyloxyalkyl, and S-based k- and amine-based S The base is with an acyl, a burnt oxycarbonyl group, an amino acid group, a phosphate or a sulfate. The above-mentioned added group is an example and has not been discussed in detail. The present invention can also be applied to the production of other known but different drug precursors. The range of drug precursors of the compound of formula I thus produced falls within the scope of the invention. The drug precursor must have some chemical conversion to produce a biologically active compound or a biologically active compound precursor. In some instances, drug precursors are biologically active, but are generally less active than the drug itself, and can be used to improve drug efficacy and safety by improving drug bioabsorbability, pharmacokinetic half-life, and the like. The combination of life and sex includes anticancer drugs and antiviral drugs. "Ring Γ, 3'-propane vinegar,," "cyclic 1,3-propane vinegar",,, ring-shaped 丨, 3_ 炫 》 基 vinegar and ring 1,3 · propyl ketone g" Refers to the following compounds:

'Promotion' refers to the improvement or addition of special characteristics. Gary is the amount of increase in the production of a particular isomer in a reaction. "Pharmaceutical (pharmaceutical) acceptable salts, including chemical formulas including chemical illusions Derived salts of the compounds of the invention in combination with an organic or inorganic acid or test compound are therefore safe for use in animals. Suitable acids include acetic acid, oxalic acid, benzoic acid (+)_7,7-bismethyl-2-oxobis% [2.2.1] heptane _1_A calcination acid, citric acid, I2· Ethylene, acid, dodecyl sulfonic acid, fumaric acid, sugar heptanoic acid, gluconic acid, glucuronic acid, hippuric acid, hemiacetic acid, desert hydrogen, hydrochloric acid, moth hydrogenated hydrogen, 2-hydrogenated ethyl ether, lactic acid , lactobionic acid, maric acid, a hospital, acid, methyl bromide, methyl sulphate, 2 benzene sulfonic acid, wall acid, oleic acid, 4,4, 曱 二 [ [3_ fluorenyl xylenol ], dish acid, polygalacturonic acid, stearic acid, succinic acid, sulfuric acid, rosinic acid, tannic acid, tartaric acid, terephthalic acid and p-toluene acid. Abbreviations and popular names for well-known chemical substances mentioned herein and in the scope of the patent are provided below. CH2C12; dichloromethane or mercapto chloride DCM; dichlorodecane (~)-DIP-Cl; (a)-β-chlorinated diisopinocampheyl 曱borax compound DMAP; 4-dimethylaminopyridine DMF; dimethyl hydrazine Indoleamine HC1; hydrogen chloride KI; potassium telluride MgS04; magnesium sulfate MTBE; decyl tertiary butyl ether NaCl; gasified sodium NaOH; sodium hydroquinone

PyBOP; benzotriazole small group-oxytripyrrole squamous TEA; triethylamine THF; tetrahydro η 夬 TMC1; gas trimethyl sulfhydryl bis POM ΡΜΕΑ; bis (trimethyl ethoxymethyl) _ 9_(2_ 醯 methoxyethyl) adenine (Adefovir dipivoxil) Well-known drug abbreviations and popular names mentioned herein and in the scope of the patent are provided below. PMEA; H2-phosphonium oxyethyl) adenine (Adef〇vir) (R)-PMPA; R-9-(2-phosphonium methoxypropyl) adenine (Tenofovir) -(2-phosphonium methoxyethyl) adenine and R-9-(2.phosphine methoxypropyl) adenine ring 〗 aryl group _u_ The stereochemical structure of the composition. The compound produced by the synthetic stepping of the present invention is a ring of adenine and vein (2-phosphonium methoxypropyl) adenine with a _ 立立航学结构 9_(2_Hao f County ethyl) adenine Yarn phenyl propylene vinegar. In the present invention, the carbon molecule on the methine imine in the chemical stereostructure of the cyclic aromatic group is defined as the first carbon ((3)' is synthesized by mutual manipulation of the palm] The aryl-u-dediol, for example, 15 1324931, is reduced by the palm of the keto acid intermediate. The other part of the present invention is to illustrate that the molecules of the phosphorus on the chain have a chirality to produce a cis-non-correspondence. The determinant of the structure is to explain that the cyclic phosphonate bond is opposite to the diol. The chemical reaction mixture is the reaction temperature and the order of adding the palmitic diol and the protected lysine dihydrate. The rest of the month is described as protecting the nitrogen that is connected to the sixth element in the lower ship.

Further, the concentration of the isomer of the reaction can be increased by adding a human extract to the selective crystallization of the acid salt, and the forward direction of the present invention refers to a ring-shaped dynamite. Key touch _ material base key geometry. A further step-by-step method of increasing the concentration of the forward isogenic lions is by recrystallizing the additional salts of the acid. Synthesis of a cyclic i•aryl-u having the desired chemical stereostructure 9-(2-phosphonomethoxyethyl)adenine and R-9-(2-phosphoniummethoxypropyl)adenine Propane ester is a polymeric synthesis step that begins with a gas molecule on adenine and a halogen-substituted benzene ring. The finally synthesized compound has two stereocenters, respectively. (1) The carbon molecule on the methine is defined as the first carbon molecule (C1) in the stereoisomer structure, and (2) 16 disc molecules on the phosphonate chain. The chiral acid intermediate produced by the citrate intermediate at the first carboniferous position of the chemical stereostructure has a chiral 7+ scale enantioselective combination with _acid and palmitic diol. The forward isomer of the present invention, the cis is the relationship between the phosphorus-carbon bond on the cyclic phosphonate chain and the isomer of the carbon-phenyl bond, via the choice of _ The product obtained after the crystallization extraction. Preparation of the compound of the present invention The preparation of the compound of the present invention is a preparation for the replacement of the prosthetic compound, which is a substitution of 9-(2.phosphine methoxymethoxyethyl) (tetra) quinone on a hexacyclic guanidine, 3 bis-diester drug precursor. , its analogues are shown in the chemical formula

Here: Μ and V are mutually compliant, and the coffee is a phosphonic acid selected from the group consisting of ruthenium phosphine and methoxy methoxy group; v is a stupid base, which can be used as a secret. Replacing U2 fluorine, gas, and bromine molecules; and being a salt that is acceptable for learning. The other part of the present invention is a chemical compound: V 丄J厶丄

Chemical Formula II Here: ^_〇迟2 is the phosphonic acid selected from the adenine group containing the methoxylate adenine "phosphine methoxypropyl" adenine; V is a stupid ring, 1-2 fluorine, gas, and bromine molecules can be arbitrarily replaced;

And is a pharmaceutically acceptable salt. In another aspect, it is meant that the salts of such compounds are combined with the salt of the sulphate or the succinate and the saponin. Another part of the invention is the preparation of a compound of formula II

V

Chemical formula II

Here, mp〇3h2 is a phosphonic acid containing 9·(2 fluorenyloxyethyl)adenine and gas) benzoyl)Xie scale; V is and is a pharmaceutically acceptable salt. On the other hand, it is meant that the salts of such compounds are combined with the terpene sulfonic acid. 18 Another part of the invention is the preparation of a compound of the formula ν 0, 〇 / ν’

Μ,〇〇" Chemical Formula II Here: _〇3 is also - containing 9-(2-phosphonium methoxyethyl) adenine and (R) 9 fluorene phosphine methoxypropyl) gland The sulphate selected by the steroid group; v is 2 bromophenyl, and is a pharmaceutically acceptable salt. ~ The other aspect refers to the combination of the salt of the compound with the leuco acid. Synthesis of propylene-1,3-diols A number of synthetic methods are known for the preparation of u-diols. These suitable methods can be divided into the following two categories, namely 丨) racemic _ _ (aromatic Synthesis of diols; 2) synthesis of palmitic 1-(aromatic hydrocarbon)-propane _, 3-diol. 11 racemic 丨 _ (aryl) · C Synthesis of calcined-1,3,-diol The 13-dihydroxy compound can be synthesized by several well-known synthetic methods in the literature. The substituted aromatic aldehyde can be esterified and reduced via lithium enolate with the addition of an alkyl acetate. (eg, Path A) for the preparation of racemic 丨·(aryl)propane•1,3-diol (Tumer, j 〇rg Chem 55:4744 (199〇). Another preparation method is 'Aromatic Green Nano-reagent can also be added to 1-propanyl propane-2- To 1-(3⁄4• succinyl substituted) propyl _1,3-diol (path B). This method can promote the conversion of different substituted aromatic hydrocarbon halides into (aromatic substitutions - C 19 1924931 alkane - Glycol (Coppi et al., J. Org. Chem. 53: 911 (1998)). Aromatic hydrocarbon halides can also be used to synthesize 2-substituted displaced propane diols by Heck coupling reaction with 1, Reduction of 3-dioxo-4-ene in combination with hydrolysis (Sakamoto et al" Tetrahedron Lett. 33:6845 (1992)). Pyridine, quinine

Ning, isoquinine propane _3·alcohol derivatives can be oxidized to substituted-diols by N-oxide formation in acetic anhydride recombination reaction (path Q (Yamamoto et al., tetrahedron 37:1871 (1981) )). Different types of aromatics can also be converted to 1-substituted-1,3-diols (path D) by the addition of a vinylineine reagent and a hydrogen-thixonation reaction.

Aiyl, R = Alkyl, R· = benzyl, M=Mg or Li, X=Halide or null aryl 'R=alkyl, R,=phenyl, magnesium or lithium, χ=halogen or 1.2 pairs Synthesis of 1-(Aromatic)-propane-1,3-diol: The analytical analysis of various known secondary alcohols produced by chemical or enzymatic methods can be used for the preparation of diol image isomers ( Harada et al., Tetrahedron lett. 28:4843 (1987)) Displaced 3_aromatic oxypropionic acid or a metal-based catalyzed 20 hydrogenation conversion reaction to an efficient preparation for efficient preparation of optically pure Synthetic Asymmetric Catalysis, Jacobsen, EN, Pfaltz, A., Yamamoto, H. (Eds), Springer, (1999); Asymmetric Catalysis in Organix Synthesis, Noyori, K John Wiley, (1994)). This type of hydroxy acid or ester product can be further reduced to produce the desired 1_(aryl)-propanone-oxime, 3-diol (path Α). The cold keto acid or ester acceptor of the hydrogen shift reaction can be prepared in different ways, such as the condensation reaction of acetophenone with the dimethyl carbonate in the presence (Chu Et al., J. Het Chem. 22:1033 (1985)), by condensation of esters (Turner et al., J. Org. Chem. 54: 4229 (1989)) or a halogen-free halogenation reaction Prepared (Kobayashi et al" Tetrahedron Lett. 27:4745 (1986)). Another preparation method is that the pure n diol on the mirror image isomer can be prepared by a reduction reaction of a derivative of /5-hydroxyethyl aryl ketone or a keto acid derivative with a boron hydride compound (path B). (Ramachandran, et al., Tetrahedron Lett. 38:761 (1997)). Another preparation method is that cinnamool which is generally available on the market can be converted into epoxy alcohol under the catalytic reaction of asymmetric epoxidation. These epoxy alcohols are reduced by Red-Al to give a mirror image of pure iota,3·diol (path c) (Ga〇, et al., J. 〇rg. Chem. 53:4081 (1980)). Aldol condensation is another known synthesis of the 1,3-oxidized product of the palm, and its starting reactant is aromatic aldehyde (path path D) (Mukaiyama Org. React. 28:203 (1982)) 〇 1324931 vcoch2co2r

V Y VCOCH2R·

HO or HO- HO· HO-

V

D

C

VCHO

VCH=CHCH, OH

V = Aryl, R = Alkyl or H, R_ =, CH2OH, C02R V = aryl, R = thio or hydrogen, R' = methanol or tarenic acid The intermediate product of the keto acid in the basic invention is from the molecule A The benzamidine chlorine compound is substituted with a dentate molecule, and the benzamidine compound can be substituted with 1-2 halogen molecules at any position on the benzene ring. In the most suitable structure, R2 is a hydrogen molecule assuming R2 is a halogen molecule, and R2 is a hydrogen molecule assuming R3 is a halogen molecule. In one part of the invention, the molecular formula A is 3-gasbenzidine chloride, and the other part of the formula A is 2-bromophenylhydrazine. The position of the first carbon of the finally synthesized compound in the present invention at the carbon center of the secondary imine. R2 R3

The compound of the formula A is reacted with trimethyl sulphate acetate and lithium diisopropylamide (which is obtained by reacting in situ diisopropylamino with n-butyllithium) to obtain oxygen-containing _ 22 1324931 propionic acid. The hydroxypropionic acid is synthesized by reacting propionic acid with (I)-DIP-gas, and then the oxypropionic acid is reduced to the palm 1,3-diol as shown in the following formula B:

Formula B

The position of the first carbon of the formula B to the center of the palm is established in this step, and the proportion of the mirror image is obtained in the subsequent steps. Synthesis of 9-(2-phosphoniumoxyethyl)adenine (pmea) differently prepared 9-(2-phosphoniumoxyethyl)adenine and r_9_(2-phosphine with decyloxypropane Methods for adenine and its analogs have been described in many literatures (Arimilli cum fl/·, WO 99/04774; Schultze β α/., Tetrahedron Letters 1998, 39, 1853-1856; Bischofberger et al. y US 5, 514, 798, US 5, 686, 629; Holy et al., US 4, 659, 825, US 4, 808, 716, US 5, 130, 427, US 5, 142, 051) and is well known in the art. These preparation methods have been modified here to prepare the desired compound. These synthetic methods, which have been modified and unexpectedly expected, have been found to reduce both the extraction time and the purification step compared to the synthetic methods mentioned in the literature. The extraction of diethyl ether in the propionic acid of the present invention is not necessary for the next step in the synthesis process. It was also found that the ester can be deprotected without purification during this synthesis. 23 1324931 In a typical synthetic method, 'adenine is substituted with or without replacement of ethylene carbonate vinegar and a test group to produce 9-alkylethyl gem σ, followed by ~ ethane ethyl adenine and TsOCH2P (〇)〇Et2 is further burned. The last step is responsible for the hydrolysis of diethyl ether to give 9-(2-phosphoniomethoxyethyl)adenine and R-9-(2-phosphonium methoxypropyl) sulfonate and their analogs.

3. Synthesis of N6-protected double gasification 9_(2_phosphoniumoxyethyl) adenine. In another step, the chlorination of 9-(2-phosphonium methoxyethyl) adenine can be borrowed. A non-chlorinated 9-(2-phosphonomethoxyethyl)adenine which is formed by the combination of gasified ethylenedithiol and dimethylhydrazine to give a N6-protecting group. In the process of gasification, dimethylformamide not only forms a vilsmeyer chlorinated substance, but also adheres to the amine group at the sixth carbon position. This protected chlorinated intermediate was found to have readily soluble properties and improved overall yield and diastereomeric ratio of the product. The use of other protecting groups such as the imiding group, the alkoxy group, the aryl group, and the oxy group can also promote the double gasification and diastereomeric ratio of the desired product.

24 $ 1324931 4. The coupling of bis-phosphoric acid with p-palphadiol is protected by the original parent-disc acid gas and the p-pallydiol produced in a low-temperature soluble methane at a low temperature. The intermediate product of protection. 4.1 The crystallization of the forward drug precursor salt is deprotected by the coupled phosphoric acid and the position of the sixth nitrogen of the palmitic diol in a mild acidic environment and the synthesized product is crystallized as a sulphuric acid to produce a cis-positive drug. The precursor forms a mesylate salt of formula 92-93% (Formula C). The reverse isomer is the predominantly impure product, and the final product is crystallized using an alcohol such as methanol to produce a diastereomer with a purity of greater than 96%.

R ^ Molecular formula c Other acids include, but are not limited to, the following, such as sulfuric acid, tartaric acid, hydrochloric acid, phosphoric acid, tartaric acid, citric acid, maleic acid, malic acid, malonic acid, lactic acid, oxalic acid Etc., the yield of the product and the ratio of the isomer can be increased. This step for synthesizing this 9-(2-phosphoniumoxyethyl)adenine can also be applied to the synthesis of other PME or (R) 9-(2-filled propyl) derivatives. . 4.2 9- {2-[2,4-cis-(S)-(+)-4-( _ benzene)·2·oxy-1,3,2-dioxy-phosphonium-2-yl]曱Synthesis of oxyethyl} adenine methanesulfonate: 25 9-{2_[2,4-cis-(SH+>4. stupid) money·dioxinan·2_yl]曱oxy B The basal thoracic acid (formula c) is synthesized via eight steps, starting with adenine and gas benzene polymerization synthesis sequences. The final synthesis product (Molecular Formula Q consists of two stereocenters, respectively (1) the first carbon on the methine and (2) the phosphorus molecule on the ring-shaped Wei chain. The diastereoisomer of the original and the palm diol (4) The chemical stereostructure of the palm-reducing reaction of the intermediate product and the palm molecule on the first carbon is selected. The isomers are referred to the relationship between the isomers and the ring. The phosphorus-carbon bond and the carbon-stup bond on the acid chain of the dish are obtained by selective crystallisation of the methyl _ _ acid salt. The starting synthetic raw materials for the palm diol and the original have been obtained. The modified step is synthesized. The palmitic diol is synthesized by a 3-step chlorination gas in three steps, and the original acid is synthesized by adenine in four steps. The finally obtained high-purity forward stereoisomer is via An unknown coupling step couples the ortho succinic acid and palmitoyl glycol to produce the final stereoisomer product. 9-(2-phosphonium methoxyethyl) adenine and racemic diol utilize a dehydrating agent such as bicyclic Hexylcarbodiimide and benzotriazole hexafluorophosphate_丨-yl-oxytripyridyl. The action in the solvent is generated and the temperature must be (at least 100 degrees Celsius) to complete the aforementioned coupling. These reactions are carried out in a relatively small amount of non-reciprocal isomers (desired isomerism) 5-10%). Unexpectedly and surprisingly, the degree of improvement in the amount of non-reciprocal is exceeded when the reaction temperature is lower at 26 degrees. This part of the invention is due to dichloroactivation. 9_(2_phosphonium methoxyethyl) gland 7 This is a more reactive chemical action. The inventors intend to combine 9-(2-phosphonomethoxyethyl) adenine with The diol is at a lower temperature. The double gasified 9-(2-fine! oxiranyloxy) adenine is prepared by standard chlorination. The gasification is low in solubility. Therefore, the coupling reaction is complicated at the low temperature. Correspondingly, the inventors sought to protect the solubility of the gas in the sixth nitrogen. The preferred protecting group for the towel is nitrogen-(dialkylamine). Methyl imine). Nitrogen alkyl fluorenyl imine) _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ --alkyl amide amine such as dimethyl hydrazine _, dimethyl acetamide, dimethyl butyl hydrazine, N-fluorenyl bite or N-methyl ketone oxygen-nitrogen land (Huafu In the environment with helium oxalate in dioxane.

5.0 Effect of the addition of two vapors and temperature: The higher the grade of the brewing amine (diethyl and higher) produces a more lipophilic dichloride. This lipophilic can make the two gas smoldering gas 27 / valley solution better. The addition of the racemic diol to the dichlorinated intermediate product in an environment of excess triethylamine can complete the reaction, but the reaction crucible is found to have an amount corresponding to the amount of the corresponding non-reciprocal isomer. In the present invention, if the reactants are added in the reverse order (digasification is added to the diol/test mixture), the amount of non-corresponding is exceeded (forward: reverse = 72: 29). It is striking that the inventors have found that the addition of reactants to the -low temperature method can increase the amount of non-reciprocal isomers such that the product tends to produce an isomer. The results are shown in Table 1 (eg, items 1-3).

Cis trans cis= forward, trans=reverse

Cis=forward, trans=reverse 28 ----- item R group • lysine--methyl-l-fluoromethane 2 methyl-anthracene--methane 3 methyl--***-S ^·--- methane 4 methyl ~~---_ one gas-----_ ------- methane 5 ethyl--one mouse-methane 0 -50 -50

Collapse: Reverse Chloride added to two 75:25

The gasification was added to 71:29 63:36 57:42 66:34 and the gasification was added to the diol-alcohol plus the addition of the two-gas mixture to the mixture "Table - also the decrease in the degree of dish * achieved. As shown in item 1_3 The two vapors are unpredictable by the addition of human diol, and the dichloride is still more suitable for the conversion of the rich. When the R of New County is methyl, the resulting two vapors are still in the mud needle. Surprisingly, the addition of the micro-excession time (U equivalent), the two vapor mud is decomposed. This 29 ^ 24931 may be due to the neutralization reaction of one equivalent of hydrogen chloride, resulting in free base dichloride ratio two The solubility of the vaporized bismuth ruthenate is high. After the crude chain reaction mixture is produced, it is placed in a water/dioxane broth and the extracted coupling mixture is reacted in alcohol with acetic acid reflux to affect the nitrogen deprotection group.

(Inward: Reverse = 75:25) (Inward: Reverse = 75:25) 5.1 Formation of the Isomer Salt and Solvent: When the coupling/deprotection sequence is completed with the reaction to palm diol ( s or R), it was observed that the amount of the non-reciprocal is exceeded (50%), and it was found that the contiguous mirror isomer did not produce a knot day during the course of the reaction. Surprisingly, the forward direction: the formation of certain salts of the reverse mixture ratio of 75:25 causes the desired diastereoisomer to crystallize. The amounts of the salts used for the preparation and the non-reciprocal isomers in the solid state and the filtration are shown in Table 2. 30 Table 2 Anisotropic salts and crystallization solvent salts Free bases lysing ~~~----- Solid state (forward: reverse) 75:25 Filtration (frequency: reverse) Succinic acid ethanol 82:18 70:30 L-tartaric acid ethanol 70:30 85:15 D-tartaric acid ethanol 76:24 77:23 Maleic acid ethanol 66:31 88:12 decane sulfonic acid ethanol: acetone 93:7 57:43 L-Succinic acid B Sf·: Propionate 56:43 93:6 D-Succinic acid ethanol: Propylene 56:43 95:2 Forward: Reverse mixture ratio 75:25 of smoldering acid The salt can produce the most desirable cis-diastereomers (93:7). The deprotection can be accomplished by adding a weak acid such as acetic acid in an alcohol solvent followed by, for example, ethanol, methylation, after deprotection Adding a reaction such as a solution. It is found that the selectivity of the acid anhydride is crystallized from the desired diastereoisomer phase. The crude methylate usually contains only 5-7% of the reverse phase isomer, and The final crystallization can reduce the reverse isomers by 1-3%. Table 3 tries to list some of the solvents in the crystallization solvent. In the solvent containing 4% reverse phase · _ sample transfer, the isomer Amount Was added. Finally, the solvent of crystallization Table 3

The volume in the table is used per gram of sample. The compounds used in the present invention and their preparation can be further understood, and the synthesis steps of these examples illustrate how these compounds are prepared. The examples are not intended to limit the invention to the scope of the invention, and various claims may be claimed in the scope of the invention.洛洛 [Implementation] Shell Example 1. Preparation of 3-(3-phenylphenyl) 3 oxy-propionic acid (1) A 12 liter 3-neck round bottom flask was bottled on an automatic stirrer, 32 and placed in a funnel (2 liters). The helium gas is filled with a bottle and added with diisopropylamine (636 ml) and tetrahydro-seven (speaking liters). The job is cooled to minus 20 degrees Celsius. Slowly add a positive τ wire (1 8 metric 2 5 molar concentration in the Hyun Hyun), and keep the temperature between minus 2 degrees Celsius and minus 28 degrees Celsius. After the total addition (30 minutes), the funnel was rinsed with hexane (3 mL) and the temperature of the stirred solution was reduced to minus 62 degrees Celsius. Then slowly add trimethyl sulphate (300 grams) and maintain the temperature at minus 6 degrees Celsius. After the completion of the addition (about 30 minutes), the cake was ls minutes at minus 6 degrees Celsius. Slowly stir to add 3-vaporized benzamidine (295 liters) and maintain the temperature at minus 6 degrees Celsius. After the addition was completed (about 65 minutes), the cooling ice bath was removed, and the reaction solution was further stirred at 1.25 λ!, while the temperature slowly rose to Celsius. The reaction flask was placed in an ice bath to cool, and water (18 liters) was added to the solution in the batch. The reaction solution was stirred for 10 minutes and diluted with decyl-tert-butyl ether (1 liter liter). The lower water soluble age axis was turned over - a round bottom flask mounted on an automatic scrambler. Mercapto-tert-butyl ether (18 liters) was added, and the stirred reaction solution was cooled to below 1 degree Celsius in an ice bath. Concentrated hydrochloric acid (300 ml of a 12 molar solution) was added and stirred vigorously. It was acidified by adding concentrated hydrochloric acid (30 ml) to the aqueous phase and extracted again with methyl t-butyl ether liter. Combined with methyl tert-butyl _ extract, rinsed with approximately 1% sodium chloride solution (1 liter), dried (magnesium sulfate, 7 gram), filtered and concentrated under low pressure to give 827 grams of yellow solid . This unpurified solid was slurried in burnt (2.2 liters) and transferred to a round bottom flask equipped with an automatic scrambler. The mixture was stirred for 1 hour below 1 degree Celsius, then the transition was washed with burnt (4 x 100 ml) and dried to the same weight (3 hours of mercury column 'room temperature' Μ hours). The sample was analyzed by a magneto-hydrogen spectrometer' and all subsequent samples were analyzed using a Van Ryan Gemini 2 〇〇 megahertz spectrometer. The sample was dissolved in the indicated solvent and the chemical shift was used as an indicator of the residual solvent. Recycling = 309 grams

Light yellow powder 1 (68.6%). Magnetic Vibration Hydrogen Fluorescence Analyzer (Acetone H); 3 = 4.1 (s, 2 hydrogen), 7.5-8.1 (m, 4 hydrogen) Example 2. (S)-3-(3-气本)-3-怪Preparation of propylpropionic acid (2)

A 12 liter 3-neck round bottom flask was placed on the automixer and placed in a leak (1 liter). The flask was filled with nitrogen, and 3-(3-phenylphenyl)-3-oxopropionic acid (275.5 g) 1 and dichloromethane (2.2 liter) were added. A temperature sensing rod was immersed in the reaction solution, and the reaction liquid was cooled to minus 20 degrees Celsius. Triethylamine (211 ml) was added over 5 minutes until all solids dissolved. Add (1) _B_ gasified borane compound) (1.60 molar concentration '1.04 liters) of dioxo-dissolved 34 1^24931 solution to the funnel, slowly add and stir to maintain the temperature below 2 degrees Celsius to minus 25 degrees Celsius between. After the addition was completed (about 35 minutes), the solution was placed in ice-cold (2-3 degrees Celsius) and warmed up and stirred. After four hours of agitation, analysis by NMR showed that the starter 1 content was less than 4%. The remaining starting material I was measured by proton nuclear magnetic resonance spectroscopy as follows: A 0.5 liter sample of the reactant was taken, and the reaction was terminated by adding water (〇 5 ml) and a 3 molar concentration of sodium cerium oxide solution. The terminated reaction solution was kneaded to separate it. The aqueous phase was acidified with 2 mL aqueous HCl (1 mL) and extracted with EtOAc (EtOAc). The organic phase was separated, filtered with a pad of magnesium sulfate and evaporated. The residue was dissolved in dichloromethane' and the solvent was evaporated with nitrogen. The residue was dissolved in acetone' and analyzed by a magnetic resonance hydrogen spectrometer (acetone-6). Water (1.2 liters) was forced into the turbid orange reaction mixture, followed by a 3 molar aqueous solution of sodium hydroxide (1.44 liters). The mixture was vigorously sifted for 5 minutes and then transferred to a separatory funnel. The different layers were separated and the basic aqueous phase was washed with ethyl acetate (1 liter). The aqueous phase was acidified with tearing hydrochloric acid (300 mL) and then extracted with ethyl acetate (twice, 3 liters each time). The two acidic ethyl acetate extracts were combined and washed with a 10% sodium sulphate solution (6 mL) dried over magnesium sulfate (130 g), filtered, and concentrated under reduced pressure to afford 328 g of a yellow oil. The standing is allowed to cause crystallization. The resulting crystals were added to ethyl acetate (180 mL) to afford turbidity and then transferred to a 2 liter, three-neck round bottom flask equipped with an automatic stirrer. The stirred ethyl acetate solution was cooled to below K) (ice bath) and then diluted with hexane (hexane). The mixture was placed in an ice bath for _4 hours and passed. The solid was collected and washed with 4:1 hexane: acetic acid (three times, 5 liters each time), and then dried to a weight of 1 (_3 〇p-inch mercury, room temperature, 12 hours). Recovery = 207.5 g of white powder 2 (74.5%) Magnetic resonance hydrogen spectrometer (C-Aeration 6): δ = 2 7 (d, J = 6 Hz, 2 gas), 4.7 (d, J = 4 Hz, 1 Hydrogen), 5H2 (nu hydrogen), 7 2 7 5 (m, 4 nitrogen). Example 3: Preparation of (S)_(-)-l-(3-phenylphenyl)_1>3_propanediol (3) A 12 liter 3-neck round bottom flask was placed in an automatic stirrer with a funnel (2 liters) And a thermometer. The flask was filled with nitrogen, and (8)_3_(3 gas phenyl)_3·#!-propionic acid 2 (2 〇 6.7 g) and tetrahydrofuran (85 〇 ml) were added, and the stirred solution was cooled to 5 ° C (ice bath) ). Will be dissolved in tetrahydrogen! The molar concentration (2.14 liters) was slowly added through the funnel to maintain the temperature below 1 G Celsius. When it is fully added (about - hour), remove the ice, so that the solution is mixed for one hour at the temperature. Water (_ml) was carefully and slowly added to terminate the reaction, and a 3 molar aqueous solution of sodium hydroxide (850 ml) was added. The mixture was stirred for 1 minute and the mixture was moved to a separation funnel when the temperature was raised to 40 degrees Celsius. The different layers were separated and the aqueous phase was extracted with ethyl acetate (600 mL). The combined organic phases were washed with 1% aqueous sodium hydroxide solution (500 mL), dried (EtOAc, EtOAc, EtOAc). The oil was subjected to preliminary analysis by a magnetic hydrogen spectrometer (氘·Trichloromethane). The oil was purified by vacuum fractionation to collect a liquid separation of 125-155 degrees Celsius / 0.15 mmHg. Recovery = 180.9 g Colorless oil 3 (94.0%). Magnetic Vibration Hydrogen Spectrometer (CDC13): δ = 2.9-3.1 (m, 2 hydrogen), 2.5 (bs, 2 hydrogen), 3.9 (t, J = 5 Hz, 2 hydrogen), 4.9 (dd, J = 7.4 , 4.8 Hz, 1 hydrogen), 7.2-7.4 (m, 4 hydrogen). The measurement step of the image isomer (ee) is carried out by chiral high performance liquid chromatography analysis, and the diol (3) is derivatized into diacetate by the following method: diol (3) (5. 〇mg, 0.026 mmol) dissolved in di- methane (2.0 mL). Add acetic anhydride (15 μl, 〇15 mmol) and 4 (dimethylamino) to a bite (丨3 mg, 0.10 mmol) and stir at room temperature for 15 minutes. The reaction was quenched by the addition of 1 mL aqueous hydrochloric acid (3 mL). The residue was dissolved in methanol (1 mL) and analyzed by chiral high performance liquid chromatography. It is surprising that the image isomer (ee) > 98% of the measured diol (3). Back-performance liquid chromatography conditions: 37

丄J Chromatography column: ·e covalent (S,S) Whelk-0 10/100 KromFEC, 250 X4.6 mm; mobile phase = 7 〇: 3 〇, sterol: water, consistent ratio from start to finish , flow rate = 1.5 liters / minute; injection volume = 1 〇 microliters, UV detection at 220 nm. Flat residence time: s-diol (diacetate) = 121 minutes, R_diol (diacetic acid) = 8.6 minutes.

Example 4. Preparation of diethyl sulfonyloxymethylphosphonic acid diethyl ester (4) A 12 liter 3-neck round bottom flask was placed in an automatic stirrer, connected to a condenser, a thermometer and a heating furnace. The flask was filled with nitrogen, and diethyl phosphite (554 g), trimeric furfural (142 g), toluene (2 liter) and diethylamine (53 ml) were added. The mixture was stirred at 85 ° C for 9 〇 and then heated back to 々IL for 1 hour. The resulting yellow aqueous solution was cooled to 4 ° C in an ice bath, and then p-toluene was added to chlorobenzene (718 g). The condenser was replaced with a funnel and triethylamine (75 mL) was slowly added while stirring, maintaining the temperature below 10 °C. After the entire addition process was completed (45 minutes), stirring was continued for 14 hours at room temperature. The mixture was filtered and the material on the filter paper was washed with benzene (2 times, 250 ml each time). The filtrate and the rinse were mixed and rinsed with water (2 times, 1 liter each time), dried (magnesium sulfate, 2 gram), filtered with diatomaceous earth (Celite 521 'No. 61790-53-2), and Concentrate under reduced pressure. 38 1324931 • » Recycling = 1004 grams Turbid yellow oil 4 (77.6%). Magnetic resonance hydrogen spectrum analyzer (trioxane). δ = 1.3 (t, J = 8 hydrogen, m, 3 hydrogen), 2.4 (s, 3 hydrogen), 4.0-4.2 (m, 4 hydrogen), 7.2 (d, J = 8 Hz, 2 hydrogen), 7.8 (d, J = 8 Hz, 2 hydrogen). Example 5: Preparation of 9-(2-ethylidene) gland beta ticket (5) A 12 liter 3-neck round bottom flask was placed in an automatic stirrer, connected to a condenser, a thermometer and a heating furnace. The flask was filled with gas, and then adenine (504 g), ethylene carbonate (343 g), dimethylformamide (DMF, 3.7 liter), and sodium hydroxide (7.8 g) were added. The mixture was heated to reflux (about 80 minutes to reach reflux, hot pot temperature = 145 ° C), and heated to reflux for 2 hours. Remove the furnace and allow the yellow aqueous solution to cool to below 100 degrees Celsius. The resulting mixture was placed in an ice bath and cooled to below 5 °C and diluted with a stupid (38 liters). The mixture was stirred at below 10 ° C for 2 hours and then filtered, and the solid was collected and washed with toluene (2 times, 0.5 liter each time) and cold ethanol (15 liters), and then dried to a weight stable (-30 吋Hg' 5 degrees Celsius, 14 hours). Solid 5 was analyzed by high performance liquid chromatography and a magnetic resonance spectrometer (dithiol oxide-氘6). High performance liquid chromatography conditions: 39 1324931 an emulsified hair column (particle size '10 microns) (Phenomenex Bondclone) 10 C18 column '300X3.9 mm; mobile phase: solvent a = 20 millimolar concentration disc acid clock 'Acid value 6.2; solvent B = acetonitrile; gradient: 〇_6〇% B / 15 minutes, 60-0% B / 2 minutes, 0% B / 3 minutes.; detection with ultraviolet light of wavelength 270 nm . Retention time: product = 6.5 minutes '3_ meta isomer (experimental) == 5.6 minutes. Recycling = 624 grams. Light yellow solid 5 (93.3%). Magnetic Oxygen Spectrometer (Dimethyl Oxide 氘6): δ = 3 6_3 8 (m, 2 hydrogen), 4·1 (t, J=6 Hz, 2H), 5.0 (bs, 1 hydrogen) , 7.2 (bs, 2 nitrogen), 8 〇 5 (s, i hydrogen), 8.10 (s, 1 hydrogen). Example 6: Preparation of 9-(2-diethylphosphonakimethoxyethyl)adenine (6) A 5 liter 3-neck round bottom flask was placed in an automatic stirrer and attached to a thermometer. The flask was filled with 9·(2 ship base chest 5 _ gram) and dimethyl ketone amine _ liter). The stirred reaction was placed in a secret and cooled to a temperature of Celsius ~. Side wheel, anti-listening at room temperature for a few hours and a slightly mixed aqueous solution. Place the funnel (2 public frequency on her and place it in an ice bath to cool it to 5 degrees Celsius. Diethyltoluene xanthine oxymethyl salt (1) 3 gram) in two brewed 40 1324931 (700 ml In the solution, slowly add while stirring, and maintain the temperature below 10 degrees Celsius. After all the additions were completed (2 hours), the ice bath was removed and allowed to mix at room temperature for 1 hour. The degree of completion of the reaction was determined by high performance liquid chromatography. Take 0.05 ml of the reaction solution and dissolve it in 1 ml of 2 mM molar potassium phosphate buffer with an acid value of 6.2. High performance liquid chromatography conditions: sulfur oxide chromatography column (particle size, 10 microns) (phenomenex

Bondclone) 10 C18 column, 300X3.9 mm; mobile phase: solvent A = 20 mmol concentration potassium phosphate (pH 62), solvent b = acetonitrile; gradient: 0 · 60% Β / 15 minutes ' 60- 0% B / 2 minutes, 〇%B / 3 minutes; detection with ultraviolet light at a wavelength of 270 nm; injection volume = 1 〇 microliter. Residence time: product 6 = 9.2 minutes 'starting reactant 5 = 6.5 minutes. The mixture was cooled to 10 ° C and acetic acid (250 mL) was added slowly. After the addition was completed (about 15 minutes), the mixture was stirred at room temperature for 30 minutes, and the temperature was gradually increased to 3 degrees Celsius. The solvent was volatilized under reduced pressure (R-152 rotary distiller, 5 mM Hg), and finally 2115 g of orange mud was left. This material was used in the next step without purification. Example 7: Preparation of 9-(2-phosphoniumoxyethyl)adenine (7) A 12 liter 3-neck round bottom flask was placed in an automatic stirrer. Unpurified 9-(2-diethylphosphonium methoxyethyl)adenine 41 1324931 6 was added to the flask, and dissolved in acetonitrile (4.0 liter) to form a slurry. The mixture was stirred at room temperature for 30 minutes and filtered. The solid material on the filter paper was rinsed with acetonitrile (2 times, 0.5 liter each time), and the filtrate and rinse were mixed and used directly in the next step. A 22 liter 3-neck round bottom flask was placed in an automatic stirrer, connected to a thermometer, condenser and furnace. After the flask was filled with nitrogen, 9-(2-diethylphosphonium decyloxyethyl) adenine 6 solution (2.59 mol), chlorotridecyl dream (1.315 liter) and moth (1,719 kg) were added. ). After the decomposing, the mixture temperature will gradually increase to 35 degrees Celsius. The scrambled mixture was warmed to 55 degrees Celsius and stirred for 1 hour between 50 and 55 degrees Celsius. The mixture was further stirred for another 3 hours while slowly cooling to 38 ° C to determine the degree of completion of the reaction by high performance liquid chromatography. High performance liquid chromatography conditions: sulfur dioxide column (particle size, 1 micron) (phen〇menex mm column; mobile phase: solvent a = 20 millimolar potassium phosphate solution, pH 6 2, solvent B = acetonitrile; Gradient: 0-60 % B / 15 min, 60 _0 % B / 2 min, 〇 % B / 3 min; detection with UV light at 270 nm. Retention time: product 7 = 5.2 min, starting Reactant 6 = 9.2 minutes. The reaction flask was attached to a funnel (2 liters), and a 35 molar aqueous solution of sodium hydroxide (4 liters) was slowly added. The temperature was raised from 32 degrees Celsius to 44 degrees. Go to the vertical separatory funnel and separate the two layers of solution. 42 1324931 The analytical liquid phase is extracted with acetic acid (2 liters) and transferred to a 12 liter 3-neck flask equipped with an automatic stirrer. Connect a funnel (丨 liter). Slowly add concentrated hydrochloric acid while stirring, and measure the acidity with a standard laboratory pH meter until the acid value is equal to 3. The resulting yellow solution is given at room temperature. 12 small B^j· 'Generate the plate. Mix the dialed mixture in an ice bath and cool to Celsius At 7 degrees, adjust the acidity to "acid test" until the acid value is equal to 3. Mix the mixture in ice-cold for 5 hours and then pass through. The mixture takes about 4 hours. The solid is collected, rinsed with acetone, and The filter funnel was air dried. A 5 liter 3-neck round bottom flask was placed in an automatic stirrer and connected to a 250 liter funnel. Unpurified solids and 1 molar sodium hydroxide solution were added to the flask ( 1.25 liters. Stir the mixture to dissolve the solids completely (15 minutes). Concentrated hydrochloric acid was added slowly until the pH was equal to 3. The resulting mixture was stirred at room temperature for 4 hours and then filtered. The solid was collected and taken with water (2 times, Rinse each time 250 ml) and propionate poo ml), dry until the weight is constant (-30 吋 Hg, 60 ° C, 14 hours). Recovery = 292 grams White solid (41.3%). Magnetic Oxygen Spectrometer (Heavy Water); δ = 3.25 (d, J = 8 Hz, 2 MH), 3.70 (t, J = 4 Hz, 2 MH), 4_10 (t, J = 4 Hz, 2 MH) , 4 6 〇 (s, 4 hydrogen 7 8 〇 (s, 1 hydrogen), 7.90 (s, 1 hydrogen). Example 8: 9-{2_[2,4-cis_(s)-(+)_4_( 3·Phenyl phenyl)_2h,3,2_-oxylanan-2-yl]methoxyethyl}Adenine Methylate (9) Manufactured 43 1324931 Prepared (Note: Dioxylated South =dioxaphosphorinan) Example 8.1: Synthesis of dichloro compounds (8)

A 2 liter 3-neck round bottom flask was placed in an automatic stirrer, connected to a condenser, a funnel (125 ml) and a heating furnace. After the flask was filled with nitrogen, 9-(2-phosphoniumoxyethyl)adenine 7 (5 gram gram), di-methane (65 liters) and N,N-diethylformamide (22.5) were added. ML). Slowly add ethylene dioxane (58.0 ml) to the stirred reaction mixture from the funnel. At this time, gas will be generated violently, and the nitrogen inlet will be removed to help the gas to be discharged. After all the addition (15 minutes), the funnel will be removed. The stirred mixture was heated to reflux for 2 hours. The solution is muddy in this process. After the reaction mixture was cooled slightly, ethylene dioxane (1.0 mL) and N,N_:ethylcarbamide were added. The addition of n,n_diethylamine can produce a gas violently. The final mixture was heated to reflux 'until all solids were dissolved (additional 25 hours, total reaction time was about 4.5 hours). The reaction liquid was analyzed by high performance liquid chromatography, showing that product 8 accounted for approximately 83%. ° The reaction was carried out to observe the formation of a dioxin compound. 44 A sample (approximately 50 μl) was taken from the reaction mixture and quenched with anhydrous methanol (1 mL) containing triethylamine. The thiol-filled acid compound produced by high performance liquid chromatography was analyzed. High performance liquid chromatography conditions: YMC-Pack R & D ' R-33-5 S-5 120A ' 250 X 4.6 mm; mobile phase: solvent A = 20 millimolar concentration phosphoric acid clock, pH 6.2; Solvent B = acetonitrile; gradient: 10-60% B / 15 min, 60-10% B / 2 min, 1 〇 % Β / 3 min; 1.4 ml / min; injection volume = 1 〇 microliter; The ultraviolet light of nm is detected. Residence time: dimethyl phosphate 11 = 8.5 minutes, monomethylphosphonate 12 = 5.8 minutes. .

The reaction solution was cooled slightly, the condenser was removed, and a distiller equipped with a thermometer, a condenser and a collecting beaker (250 ml) were added. The reaction solution was heated to reflux to collect 250 ml of the steaming liquid, and dichlorohydrazine (250 liters) was added to the reaction solution, and another 250 ml of steaming liquid was collected. The steamer was removed and the reaction flask was placed under nitrogen. Dichloromethane (100 ml) was added and diluted and placed in ice to cool. The reaction liquid was analyzed by high performance liquid chromatography, and the product was found to be 89%. High performance liquid chromatography analysis conditions: YMC-Pack R & d, R_33_5 s_5 120A, 250X4.6 mm; mobile, acid test value 6.2; solvent phase · / min WA 2 〇 毛莫耳 concentration Lin acid clock solution B B guess, gradient: 10_60 ° / 〇 B / 15 minutes, 60-10 ° / α Β / 2 minutes, 10 / 〇 B / 3 knife clock; 丨. 4 liters / minute; injection volume = microliter; with wavelength 270nm The ultraviolet light is detected. ▼Retention time: Product 8 = 8.5 minutes, starting reactant 7 = 5.9 minutes 7 Slowly add money (18 (10)) to the cake. After the addition (5 kn. Iss), the resulting light orange solution was placed on an ice bath until it was used (30 minutes). Example 8.2: Coupling reaction A 2 liter 3-neck round bottom flask was placed in an automatic stirrer and connected to a funnel (1 liter). The flask was flushed with nitrogen, and (s)-(-)-(3- phenylphenyl)-1,3-propanediol 3 (34.1 g) was added, using dichloromethane (500 ml) and triethylamine (125 ml) as solvent. The thermocouple needle was immersed in the reaction solution, and the carrier was cooled to minus 71 degrees Celsius (dry ice/isopropanol). The dioxin compound 8 was slowly added from the funnel and stirred while being added to maintain the temperature below -67 °C. When the addition process is completed for 25 hours), the ice bath is moved to 46 ° and the mixture is warmed to 0 degrees Celsius for 30 minutes. Rinse the reactants with water (55 mL) and separate the different layers. The second gas phase was diluted with acetic acid acetonitrile (500 liters) and rinsed with 5% gasified sodium hydride. The organic phase was dried with sulfur (5 Gg), concentrated with soil ((: gamma 521) and concentrated in a low pressure state with a deep red sludge of gram. The sample was dissolved in methanol.

High performance liquid chromatography conditions: YMC-Pack R & D ' R-33-5 S-5 120Α ' 250 X 4.6 mm; mobile phase: solvent A = 20 millimolar potassium phosphate, pH 6 2 Solvent B = acetonitrile; gradient: 10-60% B / 15 minutes, 6 〇 - l 〇〇 / 〇 B / 2 minutes, 1 〇 % Β / 3 minutes; 1.4 liters / minute; injection volume = 1 〇 micro L; detection with ultraviolet light having a wavelength of 27〇111^. . Residence time: wide 13 = 12.5 minutes, reverse 14 = 13.0 minutes

13 14 Dissolve the material in ethanol (500 ml) and transfer to a 2 liter round bottom flask in a magnetic stirrer, condenser and oven. Add acetic acid (55 ml) to 'and heat the red liquid to reflux 8 hour. The reaction was confirmed to be completed by high performance liquid chromatography. The sample was dissolved in methanol. 47 High performance liquid chromatography conditions: YMC-PackR & D, R-33-5 S-5 120A, 250X4.6 mm; mobile phase: solvent A = 20 millimolar concentration of phosphoric acid _, pH 6.2; solvent B = acetonitrile; gradient: 10_60 〇 / 〇 B / 15 minutes, 60_10 〇 / oB / 2 minutes, 1 〇 % B / knife, . Li, 1.4 house liter / /5.; > main shot volume = microliter; Ultraviolet light with a wavelength of 270^^ is detected. Residence time: wide 15 = 9.5 minutes, and 16 = 9.8 minutes

Target Example 8.3: 9 squad Benedictine (8) (7) Winter sulphur phenyl "oxygen-doped dioxyphosphonium 2-yl] methoxyethyl} adenine-burning acid (9) crystal one added to the appearance of the acid (21.5 ml) A precipitate formed after 15 minutes. Dilute the alcohol (400 ml) and heat until the solid dissolved (reaction pin was 70 ° C). The solution was cooled while stirring, and the sediment was formed at 46 ° C. Mix _ continue swimming for 2 hours, cool to room temperature, then set - ice bath. 5 hours. Over the cockroach and collect the solid, rinse with ethanol (2 times, 15 i liters per person) and then dry to the same weight (4) Columns, 48 55 ° '14 hours Celsius. Recovery = 49.4 grams of self-color powder 9 (51 9%). Solids contain about 6.5% of the reverse geometric isomers. PlrkIe covalent (s, s) Whelk 〇i H) / K) 0Kr 〇 mFEC250X4.6 mm; mobile phase = 55:45, methanol 〇ι % acetic acid dissolved in water; mobile phase consistent; 1 〇 ml / min iron Injection volume = H) microliter; use the wavelength to apply brain (four) light _. Sample preparation _2. 〇 gram / house rose to water. Residence time: meal (8) 5 = 246 minutes, and _ (R) 6 = 27.5 points 'Square lip ⑻7 = 18 minutes to confirm the composition of the oxide magnetic resonance spectrum analyzer (deuterium oxide) structure ..

9

Example 8.4: 9-{2-[2,4-cis-(S)-(+)-4-(3-Phenylphenyl)-2-oxo- 13»2-dioxy to South-2_yl Re-knot HH of Imethoxyethyl}Adenine Methylate (9) (Note · One Oxygen Nano=di〇Xa pJj〇Sp〇rjnan) A 3 liter 3-neck round bottom flask was placed in automatic stirring On the unit, connect the condenser, heating furnace and thermometer. Two batches of unpurified methanesulfonium salt 9 and ethanol (1.4 liters) were placed in the flask. The stirred mixture was heated to reflux (reaction pot temperature was 78 degrees Celsius) until the solids dissolved (about 1 minute). Slowly cool to room temperature and take an hour (precipitate formed at 56 degrees Celsius). The mixture was stirred at room temperature for a further 2 hours and then passed through. The collected solid was rinsed with ethanol (2 - human, 15 ml each time) and dried to the same weight (-30 汞 Hg, 65 ° C, 6 〇). Color··White solid powder purity=97% (High performance liquid chromatography) Optical purity (optical isomer high performance liquid chromatography)>99.5%. Refining point (degree Celsius): 186.5-188 unit rotation (methanol) , 25 degrees Celsius, 589 nm): +16.29 Composition: obstruction '41.58; hydrogen ' 4.56; nitrogen, 13.37 [Theoretical: carbon, 41.50; hydrogen, 4.53; nitrogen ' 13.35] Magnetic hydrogen spectrometer (heavy water) : δ = 1.30-1.60 (m, 1 hydrogen), 1.80-1.95 (m, 1 hydrogen), 2.60 (s, 3 hydrogen), 3.70-3.90 (m, 4 hydrogen), 4.10_4.50 (m, 2 hydrogen) ), 4.60 (s, 3 hydrogen), 5.15-5.40 (m, 1 hydrogen), 6.70-6.80 (m, 2 hydrogen), 7.00-7.10 (m, 2 hydrogen), 8.00 (s, 1 hydrogen), 8.1〇 (s, 1 hydrogen). Example 9: Preparation of hydrochloride via salt exchange In this invention, a precursor drug based on phosphonic acid bismuth oxalate was also formed. The salts of this prodrug can also be exchanged for other pharmaceutically acceptable salts. Oxalate is dissolved in a solution containing a high acid dissociation constant acid. A 3-neck round bottom flask was placed on an automatic stirrer, which was connected to a condenser, a heating furnace and a thermometer. Unpurified oxalate and B 50 1324931 alcohol (5-10% solution by weight) were added to the flask. The stirred mixture was heated to reflux (reaction pin temperature was 78 degrees Celsius) until all solids dissolved. The solution was acidified with hydrochloric acid and the temperature was slowly lowered to room temperature (precipitate formed during cooling). At room temperature Na mixture 'New position,. The solids containing the sharp salts were collected and rinsed with ethanol and dried in an oven to the same temperature (oven temperature = 65 degrees Celsius). Example 10: Formation of sulfuric acid by salt exchange A 3-neck round bottom flask was placed on an automatic stirrer, and the condensation, furnace and thermometer were attached. Unpurified methyl sulphonate 9 and ethanol (5-10% solution by weight) were added to the flask. The stirred mixture was heated to reflux (reaction pot temperature was 78 degrees Celsius) until all solids dissolved. The solution was acidified with sulfuric acid and gradually cooled to room temperature (precipitation formed during cooling). The mixture was stirred at room temperature and then transitioned to give the desired product. The collected sulfate-containing solid was rinsed with ethanol and dried in a vacuum oven to a constant weight (oven temperature = 65 ° C). Example 11: Formation of Sulfate by Free Base Reaction A 3-neck round bottom flask was placed on an automatic stirrer, connected to a condenser, a heating furnace and a thermometer. Unpurified acinate 9 and sodium bicarbonate solution were added to the flask. The mixture was stirred with heating until all the solids dissolved. The solution was acidified with sulfuric acid' and gradually cooled to room temperature (precipitate formed during the cooling process 51 1324931). The mixture was smashed after being scrambled at room temperature. The sulfate-containing solid was collected, rinsed with ethanol' and dried in a vacuum oven to the same weight (oven temperature = 65 degrees Celsius). Example 12: Formation of maleic acid by reaction with an anionic resin A 3-neck round bottom flask was placed on an automatic stirrer, connected to a condenser, a heating furnace and a thermometer. Add unpurified 曱 续 续 9 ° ° ° °

The mixture was stirred with heating until the solids were all dissolved. The solution containing the acid anhydride 9 was passed through an anion resin. The resulting solution contains a structural formula! The stirred mixture was gradually cooled to room temperature with a free base acidified with maleic acid (precipitate formed during cooling). The mixture was stirred at room temperature, filtered, and the solid containing the maleate was collected, rinsed with ethanol, and dried in a vacuum oven to the same weight (oven temperature = 65 ° C).

[Simple description of the diagram] 52

Claims (1)

1324931 r... Please patent scope: 'Reading' image] A preparation method of a structure I compound. Η Structure I where: Μ and V are in line with each other, Μ?. 3!! 2 is a phosphonic acid selected from the group consisting of adenine and 9-(2-phosphinylmethoxyethyl) adenine and (R)-9-(2-phosphoniumnonyloxyethyl) adenine; Wherein 'v is a phenyl group, which may be optionally substituted with 1-2 substituents selected from the group consisting of fluorine, chlorine and silk; and includes: (8) 1-arylhydrocarbon-propene-1,3-diol, wherein Aromatic hydrocarbons are phenyl substituted arbitrarily! - 2 substituents selected from the group consisting of gas, gas and moisture, and substituted with a nitrogen protecting group at the position of MP0C12纟Ν-6 at a temperature of minus 50 degrees Celsius or below ((7) upUng), wherein MPOCb is added to the aromatic propane-oxime, 3; diol; and (9) the Ν6 protecting group is removed; the presence of the para-isomer in the form exceeds the relevant trans isomer by at least 5 〇〇/0. 2. If the towel is a method of bribery, it also includes the addition of an acid to form an acid addition salt of the compound of structure I. 3. For example, the application of the fiber is the hydrochloric acid, the acid, the acetic acid, the citric acid, the cis-butanic acid, the compound 53' acid, nitric acid, phosphoric acid, succinic acid, sulfuric acid and tartaric acid. Choose among the ethnic groups. The method of claim 2, wherein the acid is selected from the group consisting of acid, succinic acid, citric acid and oxalic acid. 5. The method of claim 4, wherein the acid is a sulphuric acid. - 6. 6. The method of claim 2, further comprising crystallizing the acid addition salt. 7. The method of claim 6, wherein the solvent used to crystallize the acid is a group consisting of methanol, ethanol, isopropanol, propylene, acenaphthene and mixtures thereof. Choose among. 8. The method of claim 2, further comprising: (a) reacting the first acid addition enthalpy of the compound of structure I with the second acid having a higher acid dissociation constant than the first acid And (b) crystallization of the expected second addition of the structure I compound. 9. The method of claim 2, further comprising: (a) neutralizing the first acid addition tray of the structure I compound, (b) obtaining the free base of the compound of structure I, (c) adding A pharmaceutically acceptable acid, and 54 1324931 (6), a second acid addition disk of the structure i compound is crystallized. 10. The method of claim 2, further comprising: (8) using an anionic resin to obtain a free test of the first acid addition of the structure J compound, (b) adding a pharmaceutically acceptable acid, and (c) The second acid addition of the compound of structure I is crystallized. 11. The method of claim 1, wherein the coupling step is at or below 70 degrees Celsius. 12. If the method described in claim 1 of the patent application is included, the test is also included in (a). 13. The method of claim 1, wherein the protecting group forms a dialkylamine methine group with the nitrogen atom of the MPOCb at the N-6 position. 14. The method of claim 3, wherein the formation of the N_6 protecting group is a partial reaction to form] yip0Cl2. 15. The method of claim 13, wherein the dialkylamine-based methimine group is a dimethylamino phthalimido group, a diethylamino sulfoximine group, It is selected from the group consisting of dipropylamino sulfoximine and monobutylamino methimine. 16. The method of claim 1, wherein the structure I compound has a stereochemical isomer of structure II, 55 v U24931 Structure Π 17. Preparation method of a kind of structure ι compound: V Structure I wherein: Μ and V are in the order 'MP〇3H2 is selected from the group consisting of 9_(2_scaled methoxyethyl) adenine and (R)-9-(2-phosphonium methoxyethyl Adenine's phosphonic acid; wherein V is a 3-phenylphenyl group; includes: (8) 莩 (Chiral) 1-(3-chlorophenyl)propene- _ι, 3-diol and ΜΡ〇α2 in N. The 6 position is replaced by a nitrogen protecting group at a temperature of minus 50 degrees Celsius or below, wherein ^oc丨2 is added to the chiral 1_(3_chlorophenyl)propene The u-diol is removed; and (b) the N-6 protecting group is removed; and the intermediate isomer thereof is present in excess of the relevant trans isomer of at least 5%. 56 18. 丄JB Hyj丄18. 丄JB Hyj丄19. 20. 21. 22. 23. 24. 25. The method of claim 17 of the scope of the patent application also includes adding 酉 以 to generate the structure An acid addition salt of a compound I. The method of claim 18, wherein the acid is selected from the group consisting of succinic acid, succinic acid, citric acid, and oxalic acid. The method of claim 19, wherein the acid is nail burntin. The method of claim 17, wherein the reaction step is at or below 70 degrees Celsius. The method of claim 17, wherein the compound of the structure j has the stereochemical structure M of the structure II, and the structure of the structure II, such as the method of claim 22, further comprising adding an acid to form a structure. An acid addition salt of a compound II. The method of claim 23, wherein the acid is selected from the group consisting of succinic acid, succinic acid, citric acid, and oxalic acid. The method of claim 24, wherein the acid is a leuco acid. 57 1324931 26. The method of claim 18, further comprising crystallizing the acid into a salt, the solvent used consisting of decyl alcohol, ethanol, isopropanol, toluene, acetone, and mixtures thereof. Ethnic groups to choose. 27. The method of claim 17, wherein the N_6 protecting group forms a dimeric amine sulfhydryl imine group with a nitrogen atom of the MPOCU at the N-6 position. 28. The method of claim 27, wherein the N_6 is derived from a partial reaction to form a di-vapor. 29. The method of claim 27, wherein the dialkylamine-based sulfhydryl imine group is dimethylamino ruthenium imine, diethylamino ruthenium amide, dipropyl A group consisting of a group consisting of a group of aminimido group and a dibutylamine sulfoximine group. 3〇· A method for preparing a compound of structure I: U 〇—^ Structure I wherein: Μ and V are in position with each other, mp 〇 3H2 is selected from the group consisting of 9·(2_scaled methoxyethyl) adenine and (R)_9_(2·phosphonium hydrazide Oxyethyl) adenine phosphonic acid; wherein 'V is 2-bromophenyl; includes 58 31. 32. 33. 34. 35. (a) will be chiral 1 - (2-phenylene) ) Propylene _ 1,3_diol and MP0C12 at the N-6 position with a 1 protecting group substituted at a temperature of minus 50 degrees Celsius or below coupling reaction, wherein MPOC12 is added to the palm (chiral L-(3-Chlorophenyl)propanin_ι,3_diol; and (b) removal of the N-6 protecting group; and the presence of a meta isomer thereof in excess of the relevant trans isomer of at least 50 〇/〇. The method of claim 30, further comprising adding an acid addition salt owing to form a compound of structure I. The method of claim 31, wherein the acid is selected from the group consisting of methanesulfonic acid, succinic acid, citric acid, and oxalic acid. The method of claim 32, wherein the acid is methanesulfonic acid. The method of claim 30, wherein the reaction solution is 7 degrees Celsius or less. _ The method of claim 30, wherein the compound of structure j has a stereochemical isomer of structure II: v Structure II 59 1324931 36. The method of claim 35, further comprising the addition of an acid to form an acid addition salt of a compound of structure II. 37. The method of claim 36, wherein the acid is selected from the group consisting of brothel acid, succinic acid, citric acid, and oxalic acid. 38. The method of claim 37, wherein the acid is a sulphuric acid. 39. The method of claim 31, further comprising crystallizing the acid salt, the solvent used being selected from the group consisting of methanol, ethanol, isopropanol, acetone, toluene, and mixtures thereof. 40. The method of claim 30, wherein the n_6 protecting group forms a dialkylamine sulfhydryl imine group with the nitrogen atom of the MPOCb at the N-6 position. 41. The method of claim 40, wherein the n-6 protecting group is produced from a partial reaction to form a di-vapor. 42. The method of claim 40, wherein the dialkylamine sulfhydryl imine group is dimethylamino ruthenium imine, _ethylamino methionine, dipropyl A group consisting of a group consisting of a group of aminimine and a group of a butylamino sulfoximine. 43. A method for the conversion of acid addition salts of a compound of structure I. 60 structure I wherein = Μ and V are in position with each other, and MP 〇 3H 2 is selected from the group consisting of 9·(2_phosphonomethoxyethyl) Adenine and (R)-9-(2-phosphonomethoxyethyl) adenine phosphonic acid; wherein 'V is phenyl' may be optionally substituted with ι_2 substituents selected from a group Including fluorine, gas, and bromine; including: (a) the first acid addition oxime of the structure I compound with a second acid and the second acid reaction having a higher acid dissociation constant than the first acid, and (b) Crystallizing the expected second acid salt compound. 44. The method of claim 43, wherein the second acid is hydrochloric acid, bromic acid, acetic acid, citric acid, maleic acid, brothelin, nitric acid, phosphoric acid, succinic acid, Choose from the group consisting of sulfuric acid and tartaric acid. 45. The method of claim 44, wherein the second acid is selected from the group consisting of methanesulfonic acid, succinic acid, citric acid, and oxalic acid. 46. The method of claim 45, wherein the second acid is a hyaluronic acid. 47. A method of converting a first acid addition salt of a compound of structure I: Structure I wherein: M and V are in position with each other, and mp〇3H2 is selected from the group consisting of 9·(2-phosphinylmethoxyethyl) adenine and (r)_9-(2-phosphinylmethoxy B Alkylphosphonic acid; wherein v is a phenyl group, optionally substituted with 1-2 substituents selected from the group consisting of fluorine, chlorine and bromine; includes: (8) a first compound that neutralizes the structure I An acid addition salt, (b) a free base of the compound of structure I, (c) a pharmaceutically acceptable acid, and (d) a second acid salt expected from crystallization. 48. The method of claim 47, wherein the acid is pharmaceutically acceptable hydrochloric acid, bromic acid, acetic acid, citric acid, maleic acid, methylated acid, nitric acid, phosphoric acid, succinic acid, Choose from the group consisting of sulfuric acid and tartaric acid. 49. A conversion of the first acid addition salt of a compound of structure I V Structure I wherein: Μ and V are in position with each other ' ] ^ 〇 3112 is selected from the group consisting of 9_(2_phosphonomethoxyethyl) adenine and (8) _9_(2_phosphonium decyloxyethyl) adenine The phosphonic acid; wherein V is a phenyl group, which may be optionally substituted with 1-2 substituents, the surface group consisting of fluorine, gas, and hydrazine; includes: (a) using an anionic resin to obtain a compound of structure I Free test, (b) adding a pharmaceutically acceptable acid, and (c) crystallizing the second acid addition salt of the desired structure I compound. 50. The method of claim 49, wherein the acid is medically acceptable hydrochloric acid, bromic acid, acetic acid, citric acid, cis-butyl acid, sulphuric acid, acid, citric acid Choose from the group consisting of succinic acid, citric acid and tartaric acid. 51. The method of claim 1, wherein the N-6 protecting group and the nitrogen atom of the MPOC12 at the N-6 position form an N-6-B-B ratio than the N-1.4-oxygen group. Nalostose-based methionine or Ν-β than fluorenyl sulfoximine. 63 1324931 52. The method of claim 17, wherein the N-6 protecting group and the nitrogen atom of the MP〇Cl2 at the N-6 position form an N-hexahydropyridinium sulfhydryl group, N- 1.4-Oxygen nitrogen sulfhydryl sulfoximine or N-pyrrolidino sulfoximine. 53. The method of claim 30, wherein the N-6 protecting group and the nitrogen atom of the MP 〇Cl 2 at the N-6 position form an N-hexahydro σ ratio decyl carbamide group, N- 1.4-Oxygen nitrogen sulfhydryl sulfoximine or fluorenylpyridinyl phosphin. Pick up, schema: None. 64