Synthetic Methods and Application of Phosphoester Prodrugs

Zhihua Gong; Sha Hu; Xueping Jin; Lei Yu; Yuanyuan Zhu; Shuangxi Gu

doi:10.7536/PC211207

Progress in Chemistry ›› 2022, Vol. 34 ›› Issue (9) : 1972-1981 DOI: 10.7536/PC211207

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Synthetic Methods and Application of Phosphoester Prodrugs

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Abstract

Compared with the original drugs, the phosphoester prodrugs can not only improve the targeting, stability and bioavailability of the drugs, reduce toxicity and side effects, but also mask the unpleasant odor of the drugs, improve water solubility, and provide better access to the drugs. Phosphorylation of hydroxyl⁃containing drugs is one of the most important methods for their prodrug design. According to different valences of central phosphorus atoms and chemical structures, the phosphorylation reagents include tetracoordinated P(Ⅴ) compounds, tricoordinated P(Ⅲ) compounds and H⁃phosphite esters. The advances of these reagents in the synthesis of phosphoester prodrugs were reviewed, and the applications of these prodrugs were elaborated. Finally, the advantages and limitations of various phosphorylation reagents were summarized, and the development trend was prospected based on the application cases of continuous flow reaction technology.

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phosphoesters / prodrugs / phosphorylation / synthetic methods

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Zhihua Gong, Sha Hu, Xueping Jin, Lei Yu, Yuanyuan Zhu, Shuangxi Gu. Synthetic Methods and Application of Phosphoester Prodrugs. Progress in Chemistry, 2022, 34(9): 1972-1981 DOI:10.7536/PC211207

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1 Introduction

2 Phosphorylation reagent classification

3 Synthesis method of phosphoester prodrugs

3.1 P(Ⅴ)tetracyclic molecules

3.2 P(Ⅲ)tri coordination molecules

3.3 H⁃phosphite compounds

4 Conclusion and outlook

1 Introduction

Phosphate, as a component of the structural and functional elements of deoxyribonucleic acid (DNA) and ribonucleic acid (RNA), specifically binds to target proteins and receptors in vivo, and plays an important role in the physiological function of cells. In addition, phosphorylation is a necessary transformation process for many drugs to exert their effects in vivo, such as nucleoside drugs, which need to undergo multi-step phosphorylation to exert their effects in vivo^[1]. Drugs containing phosphate groups have been widely used in candidate, clinical and marketed drugs. There are many common phosphate prodrugs, such as antibacterial drugs such as fosfluconazole, metronidazole disodium phosphate and clindamycin phosphate, antiviral drugs such as adefovir dipivoxil and tenofovir dipivoxil, and anesthetic such as fospropofol sodium (Figure 1)^[2].

Phosphate prodrugs can improve the lipid solubility, water solubility, stability, safety and bioavailability of drugs^[3⇓~5]. Therefore, the preparation of phosphate esters is very important in drug research and development. Phosphate prodrugs are a class of prodrugs in which the phosphate group is used as the carrier and chemically linked to the hydroxyl group in the original drug structure to prepare its phosphate monoester and its salt. In terms of synthesis methods, the synthesis steps are few, and the synthesis routes and optional raw materials are more, which can meet the different requirements of laboratory and industrialization^[6]. However, there are many methods for the synthesis of phosphate prodrugs because of the differences in the structure and reactivity of various phosphorylation reagents.

In this paper, the phosphating reagents are classified according to the valence and structure of the central phosphorus atom, and their applications in the preparation of phosphate prodrugs and future development prospects are introduced.

2 Classification of Phosphorylation Reagents

Common phosphorylating reagents can be divided into three categories according to their structures and valence States of phosphorus atoms: P (Ⅴ) tetracoordinate molecules, P (Ⅲ) tricoordinate molecules, and H phosphite compounds (Fig. 2). (1) P (Ⅴ) tetracoordinate molecules, such as POCl₃, PO(OMe)₂Cl, etc., which are relatively stable and have tetrahedral geometry. The central phosphorus atom is a hard electrophilic center and can react with nucleophiles. (2) P (Ⅲ) three-coordinate molecule: It has a trigonal pyramidal structure in which there is a lone electron pair on the phosphorus atom. Therefore, the phosphorus center of these compounds is basic, a soft nucleophile, and can react with various electrophiles. However, such P (III) compounds can also react with nucleophiles when the phosphorus center is protonated or when it carries an electron-withdrawing substituent. (3) H phosphite type reagents: due to the presence of phosphoryl (P = O) and tetrahedral structure, they are similar to P (Ⅴ) four-coordinate phosphorylating reagents, but the oxidation state of the central phosphorus atom is the same as that of P (Ⅲ) three-coordinate phosphorylating reagents. However, unlike the latter, they lack a lone electron pair at the central phosphorus atom and are less susceptible to oxidation than P (Ⅲ) tricoordinated molecules. A unique feature of H phosphite compounds is the presence of P — H bonds, and the number of these phosphorylating reagents is less than that of P (Ⅴ) tetracoordinate and P (Ⅲ) tricoordinate reagents^[7].

3 Ynthesis of phosphate prodrug

3.1 Tetracoordinate P (Ⅴ) molecule

Pentavalent phosphorus compounds having a suitable leaving group are effective phosphorylating agents for certain protic substrates such as alcohols, phenols, primary amines, secondary amines, thiols, and phosphates.

3.1.1 Halophosphoric acid compound

Phosphoryl chlorides are the most common P (Ⅴ) four-coordinate structural phosphorylating agents, and phosphorus oxychloride (POCl₃), phosphorus dichloride [(RO)POCl₂], and phosphorus oxychloride [(RO)₂POCl] are the three most frequently used phosphorylating agents for the synthesis of phosphate derivatives.

POCl₃ is a cheap and easily available bulk chemical raw material with high reactivity, which is widely used in industry^[8]. Hydroxyl-containing drugs react with POCl₃ to form phosphorus oxychloride intermediates, which are easily hydrolyzed in dilute aqueous alkali to form phosphate esters. Metronidazole (1) reacted with POCl₃ without the promotion of alkaline reagent, and was hydrolyzed at room temperature for 3 H to obtain Metronidazole monophosphate (2), which was further treated under alkaline conditions to obtain metronidazole disodium phosphate (3) (Fig. 3). Metronidazole has a relatively low solubility in water (only 10 mg/mL at 25 ° C) and cannot be administered by injection^[9]. Compared with metronidazole, the solubility of metronidazole sodium phosphate in water with pH = 7 is increased by more than 50 times, which overcomes the solubility problem in the preparation of injection solution.

Florfenicol (4) is a broad-spectrum antibiotic with good activity against both Gram-negative and Gram-positive bacteria, and has been used for decades in the prevention and treatment of bacterial infections in fish, birds, and mammals^[10⇓~12]. In our previous attempt to prepare florfenicol phosphate monoester with phosphorus oxychloride as the phosphorylating agent, we unexpectedly found that the water-soluble prodrug florfenicol phosphodiester (5) could be prepared in high yield under the POCl₃/ pyridine /CH₃CN system (Fig. 3)^[13]. The achievement has obtained the Chinese Invention Patent Authorization Certificate and the Hubei Science and Technology Achievement Registration Certificate (the achievement level has been identified as "international advanced")^[14]^[15]. According to our latest research results, the solubility of florfenicol phosphate diester sodium salt in water is increased by more than 1100 times compared with the original florfenicol (water solubility is only 1.335 mg/mL).

For polyhydroxy compounds, it is often necessary to add protective groups, and then remove the protective groups after POCl₃ treatment to obtain the corresponding monophosphate. Clindamycin phosphate (8) is mostly prepared by a similar synthesis process, that is, clindamycin hydrochloride (6) is used as a raw material to protect the hydroxyl groups at the 3 and 4 positions to obtain propylidene clindamycin (7), and POCl₃/Et₃N/ pyridine is used as a phosphorylation system to obtain the final product clindamycin phosphate through a two-step reaction of phosphorylation and hydrolysis (Figure 3)^[16⇓~18]. Clindamycin phosphate has a lower logD value (logD = − 1.87, pH = 7) than clindamycin (logD = + 0.41, pH = 7) and can diffuse rapidly away from the injection site, thereby reducing pain and irritation during injection.

Phosphate can be prepared more efficiently by POCl₃ in continuous flow reaction technology and microreactor technology. In recent years, continuous flow reaction technology and microreactor technology have attracted wide attention from academia and business circles in the fields of chemical synthesis, biology and medicine due to their advantages such as high efficiency of mass and heat transfer, high space-time efficiency, good repeatability of process, continuous and automatic operation, stable product quality and safe operation. With the help of continuous flow technology, Ying Hanjie's group realized the synthesis of nucleoside phosphate by two-step reaction with POCl₃ as the phosphate esterification reagent (Fig. 4)^[19]. The method has the following advantages: (1) higher atom economy and safety, and the consumption is greatly reduced compared with a batch system; The volatilization of POCl₃ can be prevented by keeping it in a closed system all the time; (2) the reaction efficiency is high, the reaction conditions are mild, the operation is simple, and the efficient conversion can be realized without strict anhydrous conditions.

Except for phosphorus oxychloride, the phosphorochloridates shown in Figure 5 can be used as phosphorylating reagents. Buparvaquone (9) is a naphthoquinone antileishmanial drug with high lipid solubility, and the introduction of a phosphate group can increase the water solubility to improve the pharmacokinetic properties^[20]. The M Mäntylä group used the classical POCl₃ phosphorylation method without success^[21]. Instead, they used diethyl chlorophosphate as a phosphorylating reagent in the presence of sodium hydride to obtain the intermediate bupavaquinone diethyl phosphate (10) in high yield, and removed the ethyl protecting group by trimethylsilyl bromide treatment to obtain bupavaquinone phosphate prodrug 11 (Fig. 6). Compared with original drug 9, its solubility in water at pH values of 7.4, 5.0 and 3.0 was increased by more than 116 times. The selective phosphorylation of Chloramphenicol (12), a broad-spectrum antibacterial drug, is quite challenging. Spivey et al. Realized the selective phosphorylation of primary alcohol by dibenzyl chlorophosphate and o-xylylphosphoryl chloride in the presence of 2-aryl-4-( dimethylamino) pyridine-N-oxide 15 to obtain intermediate 13, and the chloramphenicol phosphate prodrug (14) was obtained by removing the protecting group (Fig. 6)^[22]^[23].

Reactions using phosphorylating reagents of the phosphoryl chloride class are generally promoted by basic reagents, including trialkylamines, pyridine and its analogs, diazabicyclo (DBU), Nalkyl azoles, and others. In addition to phosphoryl chloride reagents, phosphorofluorides with low reactivity are also used in a small amount^[24,25]. When this reagent is used for phosphate esterification, the use of DBU as a base to promote the reaction is good, but the use of trialkylamine, pyridine, etc. As a base is not good (fig. 7)^[26]. Phosphorylation using bromophosphates is rarely reported.

When the alcohol is activated by potassium tert-butoxide, thallium ethoxide, alkyl lithium, tert-butylmagnesium chloride, 5-dibutylstannoxane, etc., the rate of the phosphate esterification reaction can be greatly accelerated. The reactivity of the activated hydroxyl group is often higher than that of the unactivated amino and hydroxyl groups, which can be used to improve the selectivity of the reaction. This method is often used in the synthesis of nucleotide phosphates, and the best effect is achieved when organomagnesium reagents or organoaluminum are used for activation, and the hydroxyl phosphate esterification can be carried out with perfect selectivity without protecting the amino group of the nucleoside. For example, cytidine derivative 16 was treated with 1 equivalent of tert-butylmagnesium chloride, and its phosphate 17 was obtained in high yield by using (CH₂=CHCH₂O)₂POCl as a phosphorylating agent (fig. 8)^[27].

3.1.2 H₃PO₄ and phosphate ester

Since phosphorus oxychloride is very reactive, when an alcohol reacts with an equimolar amount of phosphorus oxychloride, it may produce phosphodiesters and triesters as by-products. Therefore, from the point of view of green chemistry, it is more attractive for equimolar amounts of alcohol and phosphoric acid to undergo a phosphoesterification reaction to synthesize phosphate monoester, because the reaction produces only water as a by-product (Fig. 9).

Barker et al. Reported the direct esterification of phosphoric acid and alcohol under high temperature and vacuum melting conditions in 1972. The conditions were too harsh, but the reaction could be significantly promoted by the use of H₃PO₄/P₂O₅ mixed system^[28]. Diphenylalkene and diphenylalkane compounds 18 (such as Combretastatin A, 4, pterostilbene, erianin, etc.) widely exist in natural products and have a variety of biological activities^[29⇓~31]. However, these compounds have poor water solubility, are basically administered orally, and have low bioavailability. Gu Jinhua et al. Disclosed in a patent a method for preparing stilbene or diphenylethane compound phosphate by using H₃PO₄/P₂O₅ as a phosphate esterification system (fig. 10), which has high yield and less pyrophosphorylated impurities^[32]. Stilbenes or diphenylethanes were reacted with H₃PO₄/P₂O₅ system at 100 ℃ to give their phosphate prodrugs 19, which were further alkalized to give the sodium salt of their phosphate esters 20. Among them, pterostilbene phosphate has good cell permeability, which leads to its increased activity^[33]. At the highest concentration tested (100 μmol/L), it showed a 6-fold induction of PPARα (peroxisome proliferator-activated receptor) compared with the original pterostilbene, and showed a stronger induction at lower concentrations, which can be used for hypercholesterolemia.

In the absence of tertiary amine, part of the alcohol is easily protonated by phosphoric acid to reduce the reactivity of the alcohol. In the presence of an equimolar amount of a tertiary amine such as tributylamine, phosphoric acid and the tertiary amine form ammonium phosphate, which does not protonate the alcohol due to its low acidity, with moderate conversion. When nucleophilic imidazole is added, the more reactive intermediate phosphoramide imidazolium salt is formed, which reacts more easily to monophosphate (fig. 11)^[34]. Phosphate does not react with the amino group in nucleoside 21 in the method of adding nucleophilic base. Thus, the hydroxyl group of the amino alcohol is selectively phosphorylated and can be used for selective phosphorylation of the amino unprotected nucleoside to give the phosphate prodrug 22.

Dibenzyl phosphate, an ester derivative of phosphoric acid, can also be used as a phosphorylating agent. The endogenous estrogen metabolite 2 methoxyestradiol (23) has attracted attention because of its anti-tumor cell proliferation effect^[35]. However, the water solubility of 2-methoxyestradiol is low, and Cushman et al. Designed 2-methoxyestradiol phosphate using a prodrug strategy to greatly improve its water solubility^[36]. The regioselective phosphorylation of 2-methoxyestradiol at the 3-hydroxyl group relative to the 17-hydroxyl group depends on the selective deprotonation of phenol under alkaline conditions, resulting in a more nucleophilic phenoxide anion. Methoxyacetylene alcohol was reacted with dibenzyl phosphite in the presence of dimethylaminopyridine and diisopropylethylamine to give its dibenzyl phosphate 24, which, after removal of the benzyl protecting group and alkalization, gave its monosodium phosphate salt 25 (Fig. 12). Intravenous administration of 1 mg/kg resulted in a more than 2-fold increase in plasma concentration in rats within 5 min compared with TC 23, and showed a significant, dose-related decrease in tumor weight after intraperitoneal administration in Lewis lung cancer metastasis model mice.

In addition, some other aryl phosphates can also act as phosphorylating agents. Among them, nitrophenyl phosphate is easy to transesterify with other alcohols to obtain new phosphate because of the good separation of nitrophenyl fragment. For example, the novel bicyclic phosphate reagent 27 is transesterified with Topotecan (26) in the presence of potassium carbonate to form Topotecan phosphate prodrugs (28) (fig. 13)^[37].

3.1.3 Pyrophosphate (or salt)

Pyrophosphoric acid (phosphoric anhydride) and diesters of pyrophosphoric acid are less frequently used as phosphorylating agents (Fig. 14), while chlorine pyrophosphate is widely used as a phosphorylating agent (Fig. 15)^[38]^[39]. Dexamethasone (29) reacts with pyrophosphate chloride at low temperature and then hydrolyzes to form Dexamethasone phosphate selectively at C21, but not at C11 and C17, which are more hindered^[40]. Dexamethasone sodium phosphate (30) was then obtained by alkalization with sodium hydroxide. Compared with the original drug 29, the solubility of dexamethasone sodium phosphate in pure water was increased by more than 500 times^[41]. The ammonium pyrophosphate can realize the preparation of nucleoside triphosphate under the action of a condensing agent^[42]. Trimethyl phosphate was used as solvent. Inosine 31 was monophosphorylated with phosphorus oxychloride and then reacted with tributylammonium pyrophosphate to give inosine 5 'O triphosphate 32 (fig. 15)^[43].

3.2 P (Ⅲ) tricoordinate molecule

Phosphorylation of alcohols can also be achieved by trivalent phosphorus reagent oxidation. P (Ⅲ) tricoordinate molecular reagents are generally more reactive than the corresponding pentavalent analogues. Therefore, this method has been widely used to prepare less reactive alcohol (such as nucleoside) phosphate derivatives.

3.2.1 Phosphorus trichloride

Phosphorus trichloride (PCl₃) is a highly reactive reagent, which reacts with alcohol at low temperature in the presence of acid binding agent to obtain the corresponding phosphite, which is then oxidized and hydrolyzed to obtain phosphate. For example, 2 ', 3' -O-isopropylidene nucleoside (33) was reacted with PCl₃ in the presence of trimethyl phosphate at 0 ° C, oxidized with chlorine, and hydrolyzed to give its 5 '-monophosphate 34 (fig. 16)^[44].

The high reactivity of the PCl₃ also allows for sterically hindered phosphorylation of tertiary alcohols. For example, Fluconazole (Fluconazole, 35) was reacted with PCl₃ in the presence of pyridine, alcoholysis followed by oxidation to give the protecting group-containing phosphate intermediate 36, and removal of the protecting group gave fluconazole phosphate (Fusi fluconazole, 37) (Fig. 16)^[45]. 37 has high solubility in aqueous solution with pH value ranging from 4 to 12, and its solubility in water is increased by more than 25 times compared with the technical 35^[46]. The administration of 400 mg fluconazole requires 200 mL of aqueous solution, whereas the administration of 400 mg fluconazole equivalent fluconazole phosphate requires only 5 mL of aqueous solution, a 40-fold reduction in the volume of solvent.

Similarly, fluticasone propionate (38), which cannot be directly phosphorylated due to large steric hindrance around the hydroxyl group at position 11, gave its phosphite 39 after reaction with PCl₃ at low temperature (Fig. 16)^[43].

3.2.2 Phosphoramidite compound

The representative compounds of phosphoramidite trivalent phosphorus reagents are N, N diisopropyl phosphoramidite di-tert-butyl ester and bis (2 cyanoethyl) N, N diisopropyl phosphoramidite, which have high activity and are widely used in the synthesis of phosphate esters^[47]. When phosphoramidite is activated by weak acids such as 1H tetrazole, 5 methyltetrazole and 5 (4 nitrophenyl) tetrazole, the intermediate phosphite is formed first, then oxidized by hydrogen peroxide or m-chloroperbenzoic acid to obtain the protected phosphotriester, and finally the corresponding monophosphate is obtained by removing the protecting group^[48]. Phosphorothioate is obtained if treated in the presence of elemental sulfur (fig. 17)^[49]. However, these reagents are expensive, and their high reactivity makes them easy to oxidize and hydrolyze spontaneously, which is inconvenient for storage.

Treprostinil is a prostacyclin analogue used to treat pulmonary hypertension associated with interstitial lung disease^[50]. However, Treprostinil usually causes injection pain when injected subcutaneously, and has a short half-life of about 1 H, regardless of the route of administration. Another disadvantage is that oral administration has a strong first-pass effect, which is about 60% in animal experiments. The half-life of the phosphate prodrug 42 in human plasma and intestinal juice was more than 2 H. TBDMS side chain triprost benzyl ester (40) was obtained by phosphorylation of Treprostinil with the protection of hydroxyl groups except the side chain, and TBDMS side chain triprost benzyl ester (41) was obtained by one-pot oxidation with m-chloroperbenzoic acid in the presence of 1H tetrazolium using dibenzyl N, N diisopropyl phosphoramidite. After desilylation and hydrogenolysis, treprostinil side chain phosphate prodrug 42 was obtained (fig. 18).

Phosphoramidites also have important applications in the preparation of prodrugs of novel coronavirus inhibitors. PF 00835231 (43) is a potent inhibitor of the coronavirus family 3CL pro protease and is selective for human host protease targets^[51]. In addition, PF 00835231 showed strong in vitro antiviral activity against the novel pneumonia coronavirus SARS CoV 2 as a single drug, and had a synergistic effect in combination with remdesivir. PF 07304814 (45), a phosphate prodrug of PF 00835231, was rapidly converted to the active metabolite PF 00835231 at a conversion rate of 75% in vivo, exhibiting antiviral activity^[52]. PF 00835231 The phosphate prodrug PF 07304814 was obtained by a two-step reaction: PF 00835231 reacted with di-tert-butylN, N diisopropylphosphoramidite in the presence of 1H tetrazole, followed by oxidation with hydrogen peroxide to give intermediate 44. Tert-butyl phosphate was subsequently hydrolyzed with trifluoroacetic acid to give the phosphate prodrug PF 07304814 (fig. 19). Compared with the original drug 43, the solubility in water is improved by more than 2000 times, and the water solubility is significantly improved, so that the dosage is more flexible in clinical application.

3.3 Phosphite compound

Phosphite and its derivatives are widely used in agriculture, industry and pharmaceutical production. For example, phosphite can react with alcohol to form phosphate, and phosphite can react with unsaturated compounds to form alkyl phosphonate under alkaline conditions.Compounds containing C — P bonds can be formed by coupling of H — phosphite with C — C unsaturated bonds under metal catalysis. H — phosphite can also participate in Kabachnik Fields reaction to synthesize α-aminophosphonates^[53]^[54]^[55,56]^[57].

It is essential to develop a simple, efficient, versatile, and low-cost method for the preparation of H phosphite monoesters. Common trivalent phosphorus reagents (Fig. 20) can effectively introduce H phosphite monoester moiety into various nucleoside compounds containing hydroxyl groups, and obtain nucleoside H phosphite in high yield (80% ~ 95%) under mild reaction conditions. The reactivity of these reagents to hydroxyl groups is different. :PCl₃/ imidazole system (46) or salicylchlorophosphorus (48) and H pyrophosphate (47) can phosphinate the 3 hydroxyl group of ribonucleosides protected at the 2 position, while H diphenyl phosphite (49) does not react with sterically hindered hydroxyl-containing substrates^[7].

Diphenyl phosphite is regarded as a versatile phosphorylating reagent for a variety of hydroxyl compounds because of its cheapness and stability. The hydroxyl-containing substrate is first converted with diphenyl phosphite to a phosphite derivative, which is then hydrolyzed to a more stable phosphite monoester intermediate, which is then converted to a phosphate^[58]. There are three common activation methods for this kind of reaction: (1) forming mixed anhydride with acyl chloride, and then forming H phosphite diester with hydroxyl-containing compound, which can prepare phosphate diester containing chiral phosphorus atom; (2) react with TMSCl to form phosphite triester, which can be oxidized to prepare phosphorothioate or selenophosphate; (3) The P — N and P — F bonds are introduced after the oxidation by I₂/pyridine/TMSCl system.

Phosphorylation reagents are finding increasing use as synthetic intermediates. Phosphorylation of nucleotides, oligonucleotides, and their analogues is challenging in terms of reaction efficiency, versatility, and mildness, and the H phosphite-based synthesis method can meet the reaction requirements. Zidovudine (AZT) is an effective treatment for human immunodeficiency virus (HIV). However, because it can not be rapidly converted to the corresponding triphosphate, it is easy to cause anemia, neutropenia and other myelosuppressive side effects^[59]. AZT and 5 '-thymidine dinucleoside phosphate (54) were used as anti-HIV drugs to detect HIV-infected MT 2 cells, and were found to have stronger anti-HIV ability than monomeric drugs. Phosphodinucleotides were prepared as shown in Fig. 21^[53]. 5 'thymine (50) was reacted with diphenyl phosphite in dry pyridine at room temperature under nitrogen, followed by hydrolysis to give 51, which was coupled with AZT by pivaloyl chloride to give dinucleoside H phosphate 52. 52 react with amino acid methyl ester in Et₃N/CCl₄/CH₃CN/H₂O solution at room temperature to give product 53, which is then deprotected with formic acid to give dinucleotide phosphate 54.

In addition to being widely involved in the phosphorylation of nucleotides and their analogues, phosphites are also widely used in the synthesis of phosphate prodrugs of other hydroxyl-containing drugs, such as catecholamines containing phenolic hydroxyl groups. Catecholamine (55) is a dopamine agonist widely used in the treatment of Parkinsonism and Huntington's disease, Alzheimer's disease, and neurological diseases and disorders^[60,61]. Sodium phosphate 58, one of the phosphate prodrug compounds of catecholamines, is prepared by the reaction of catecholamine with dibenzyl phosphite (56) in the presence of the basic compounds DMAP and DIPEA to give its dibenzyl phosphate 57, followed by palladium-carbon reduction and salt formation with sodium bicarbonate to give 58 (fig. 22)^[62].

4 Conclusion and prospect

The main purpose of prodrug design is to improve the bioavailability of drugs, increase water solubility, increase drug stability, reduce toxic and side effects, and promote long-term efficacy of drugs. Prodrug design has been paid more and more attention in new drug research. It modifies the structure of existing drugs, has clear mechanism of action, less relative risk and short development cycle. Phosphorylation is an important strategy to develop hydroxyl-containing drugs as prodrugs^[63]. Over the past few decades, pharmaceutical and chemical workers have developed a variety of phosphate reagents for the synthesis of phosphate drugs. Among them, pentavalent phosphorus reagents are stable, easy to store and cheap, so they are mainly used in the synthesis and industrialization of phosphate prodrugs, such as benzyl alcohol, phenolic compounds, hydroxyl phosphorylation on the alkyl chain. For example, the synthesis of sodium riboflavin phosphate (the monosodium salt of riboflavin phosphate) can be achieved using phosphorus oxychloride/pyridine/acetonitrile system, phosphorus oxychloride/γ-butyrolactone system, phosphorus oxytrichloride/trimethyl phosphate or triethyl phosphate system, but the reaction mechanism may be different^[64]. Phosphorylation systems must be specifically selected for different substrates. Trivalent phosphorus reagent has high reactivity and high synthesis and conversion efficiency, but it also has the problems of easy spontaneous oxidation and hydrolysis, which increases the difficulty of storage and experimental operation. Trivalent phosphorus reagents have their uses for hydroxyl-containing drugs with greater steric hindrance and less reactivity.

With the continuous progress of organic synthesis methodology and green chemistry, more efficient and green new reagents, new methods and new processes of phosphate esterification will continue to emerge. Continuous flow reaction technology can be used for more green, efficient and safe preparation and production of various phosphate prodrugs^[65]; New phosphoesterification reagents with high selectivity and high reactivity need to be further studied to solve the problem of selective phosphoesterification of polyhydroxy drugs and the difficulty of reaction of large sterically hindered hydroxyl groups. The technological progress of drug phosphorylation will bring new opportunities for drug research and development, and will also bring health and well-being to the people.

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Funding

National Natural Science Foundation of China(21877087)

National Natural Science Foundation of China(22074114)

National Natural Science Foundation of China(20602164)

Hubei Provincial Department of Education of China(2020CFB623)

Hubei Provincial Department of Education of China(2021CFB556)

Key Laboratory for Green Chemical Process of Ministry of Education Open Fund(GCP20200201)

Hubei Key Laboratory for Processing and Application of Catalytic Materials(202023504)

Hubei Key Laboratory of Novel Reactor and Green Chemical Technology (Wuhan Institute of Technology) Open Fund(40201002)

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