A process for the preparation of 7,8-dihydrobiopterin

Abstract

The application belongs to the field of chemical synthesis and particularly relates to a preparation method of 7,8-dihydrobiopterin. The application takes L-biopterin as a starting material, carries out catalytic reduction, and purifies through a preparation high-performance liquid chromatography to obtain high-purity 7,8-dihydrobiopterin (BH2). The various reagents used in the preparation method are common and easy to obtain, the operation is simple, the yield is high, the selectivity is strong, the purity of the obtained target product is high, and the method is suitable for batch preparation of 7,8-dihydrobiopterin (BH2).

Description

Technical Field

[0001] This invention belongs to the field of chemical synthesis, specifically relating to a method for preparing 7,8-dihydrobiopterin. Background Technology

[0002] Saproptorelin, also known as tetrahydrobiopterin (6) R )-BH4), chemical name: (6 R )-2-amino-6-[(1 R ,2 S )-1,2-dihydroxypropyl]-5,6,7,8-tetrahydropteridine-4(1 H )-ketone, the structure of which is shown below:

[0003] A key prodrug of sapropterin hydrochloride, a specific drug for the treatment of phenylketonuria (PKU), (6 R )-BH4 is a cofactor of phenylalanine hydroxylase (PAH). Phenylalanine (Phe) undergoes a hydroxylation reaction under the action of PAH to yield tyrosine. In PKU patients, PAH activity is weak or even nonexistent. (6) R )-BH4 can activate PAH, promote the normal oxidative metabolism of Phe in the body, and reduce Phe levels in some patients. Saproptorelin hydrochloride is a phenylalanine hydroxylase agonist developed by BioMarin Pharmaceuticals. It was first approved by the US FDA as an orphan drug in December 2007, under the brand name Kuvan. As a specific orphan drug, its clinical demand in the Chinese market has been increasing year by year after the original product withdrew from the market.

[0004] For drug developers, the main tasks include not only obtaining high-quality active pharmaceutical ingredients (APIs) and developing efficient synthetic processes, but also studying the types and sources of impurities in the APIs and how to control the generation of process impurities. Researchers typically begin by synthesizing impurities generated in the process, and then develop efficient synthetic routes for these impurities to obtain a large number of impurity reference standards, ensuring the quality testing of each batch of APIs (such as HPLC localization of impurities and determination of impurity content).

[0005] 7,8-Dihydrobiopterin (BH2), chemical name: 2-amino-6-[(1 R ,2 S )-1,2-dihydroxypropyl]-7,8-dihydropterin-4(1 H)-ketone is a specific impurity in sapropterin hydrochloride raw material. It has been included in the quality standard of sapropterin hydrochloride raw material in the United States Pharmacopeia (USP) since May 1, 2025. According to the high performance liquid chromatography detection conditions described in the pharmacopoeia, its relative retention time with sapropterin hydrochloride is 0.54.

[0006] There are few reports on this impurity; Schircks J. et al. (Schircks, J.; Bieri, JH) Helv. Chim. Acta 1978, 61 A chemical reduction method for L-biopterin was developed using sodium dithionite (2731-2737). The specific synthetic route is as follows:

[0007] The pH of this reaction is strictly controlled between 10.0 and 11.0. Too low a pH results in a slow reaction, while too high a pH can lead to substrate decomposition. Furthermore, the optimal reaction temperature is 70 °C. Too low a temperature leads to incomplete reaction, while too high a temperature can generate byproducts, making it difficult to guarantee the quality of the final product. The entire reaction must be carried out in a glove box under a nitrogen atmosphere, which is quite demanding. In practical applications, it suffers from poor selectivity and low yield, limiting its large-scale application.

[0008] Thöny B. et al. (Thöny, B.; et al. J. Biol. Chem. 2000, 347 (1), 1-16) An enzymatic salvage synthesis process was developed that uses L-mercaptoline as a starting material and bioconverts it to BH2 under the action of metoprolol reductase (SR). The synthetic route is as follows:

[0009] This method has a very small production scale, and metoprolol reductase (SR) is not a commercially available enzyme that needs to be purified before use. Standards prepared by biological enzymatic methods have risks such as high residual impurities and the introduction of impurities from unknown biological sources, which poses significant problems for application.

[0010] Another report states that Escherichia coli dihydrofolate reductase acts on 7,8-dihydrobiopterin (DHBP), which is an oxidation product of THBP (tetrahydrobiopterin), thereby converting DHBP to THBP (Watanabe et al., Seikagaku, volume 53, no. 8, p. 1008 (1981)).

[0011] JPH059065B2 discloses a 6-( RA method for preparing L-7,8-dihydrobiopterin, characterized in that L-biopterin is reduced with zinc powder in the presence of alkali, the resulting L-7,8-dihydrobiopterin is treated with molecular sieves to remove dihydrofolate reductase (DHFR) inhibitors, L-7,8-dihydrobiopterin (L-BPH2) is then reduced by dihydrofolate reductase (DHFR), and then purified by adding L-ascorbic acid and L-cysteine ​​hydrochloride.

[0012] In summary, existing methods for preparing 7,8-dihydrobiopterin (BH2) suffer from problems such as low yield, poor selectivity, high technical requirements, and high production costs, hindering large-scale synthesis. Therefore, the practical application of 7,8-dihydrobiopterin (BH2), whether as an impurity standard or a pharmaceutical intermediate, is limited. Consequently, researching and providing a new, efficient method for preparing 7,8-dihydrobiopterin (BH2) is of great significance. Summary of the Invention

[0013] In view of the shortcomings of the prior art, the present invention provides a method for preparing 7,8-dihydrobiopterin. This method is simple, highly selective, has a high yield and high purity, and is suitable for the batch preparation of 7,8-dihydrobiopterin.

[0014] This invention is specifically achieved through the following technical solution:

[0015] A method for preparing 7,8-dihydrobiopterin (BH2) includes the following steps: using L-biopterin as a starting material, under alkaline conditions, a hydrogenation reaction is carried out in the presence of a catalytic reduction system to generate a product rich in BH2; the product is purified by preparative high-performance liquid chromatography to obtain high-purity 7,8-dihydrobiopterin (BH2). The process route is shown below:

[0016] The preparation method specifically includes the following steps:

[0017] L-Biopterin was added to solvent C and stirred until completely dissolved. Then, the catalytic reduction system reagent was added, and the pH of the reaction system was adjusted to 10–12. The mixture was transferred to a hydrogenation reactor, purged with nitrogen or argon, and then pressurized with hydrogen. The reaction was maintained at this temperature until complete. The catalyst was removed by filtration, and acid D was added to adjust the pH to 6.5–7.5. The mixture was concentrated to dryness to obtain a mixed solid containing the target compound, without separation. The solid was purified by preparative high-performance liquid chromatography to obtain a pale yellow solid final product, 7,8-dihydrobiopterin (BH2).

[0018] Preferably, the catalytic reduction system reagent is composed of a metal catalyst reagent A and a poisoning agent reagent B.

[0019] Preferably, the metal catalyst reagent A is selected from one or more of palladium on carbon (Pd / C), platinum dioxide (platinum black), Raney Ni, rhodium on carbon (Rh / C), and palladium hydroxide on carbon (Pd(OH)2 / C).

[0020] Preferably, the poisoning agent B is selected from one or more of thiols, disulfides, quinolines, pyridines, amines, lead salts, and copper salts.

[0021] Preferably, the catalytic reduction system reagents are palladium on carbon (Pd / C) / thiol reagent combination, platinum dioxide (platinum black) / quinoline reagent combination, Raney Ni / pyridine / amine reagent combination, rhodium on carbon (Rh / C) / disulfide reagent combination, or palladium hydroxide on carbon (Pd(OH)2 / C) / lead salt or copper salt reagent combination.

[0022] Preferably, in the catalytic reduction system, the thiol is one of dodecanethiol, octylthiol, or benzylthiol; the disulfide is one of dimethyl disulfide or diphenyl disulfide; the quinoline is one of quinoline or isoquinoline; the pyridine reagent is pyridine; the amine reagent is one of triethylamine or ethylenediamine; the lead salt is lead acetate; and the copper salt is copper acetate monohydrate.

[0023] Preferably, the reagent in the catalytic reduction system is a combination of platinum dioxide (platinum black) and quinoline.

[0024] Preferably, the solvent C in the step is selected from one or more of water, methanol, ethanol, isopropanol, 50% methanol aqueous solution, 75% ethanol aqueous solution, 95% ethanol aqueous solution, tetrahydrofuran, 1 mol / L sodium hydroxide aqueous solution, 0.1 mol / L sodium hydroxide aqueous solution, and DMSO; more preferably, it is a 1 mol / L sodium hydroxide aqueous solution.

[0025] Preferably, the heat preservation reaction temperature in the step is 10–50°C.

[0026] Preferably, the heat preservation reaction time in the step is 4 to 6 hours.

[0027] Preferably, the hydrogenation pressure in the step is 0.5 to 4.0 atm.

[0028] Preferably, the alkali used to adjust the pH in the step is an aqueous solution of sodium hydroxide or potassium hydroxide.

[0029] Preferably, the acid D used to adjust the pH in the step is selected from hydrochloric acid, sulfuric acid, nitric acid, perchloric acid, phosphoric acid, formic acid, acetic acid, oxalic acid, and trifluoroacetic acid; more preferably, hydrochloric acid.

[0030] Preferably, the concentration of the hydrochloric acid aqueous solution of acid D in step D is in the range of 0.01 mol / L to 12 mol / L, and more preferably 4 mol / L.

[0031] In one embodiment, the metal catalyst reagent A in the catalytic reduction system is 5% Pd / C; the molar ratio of L-biopterin to 5% Pd / C (based on the metal Pd content) is 1:0.2 to 0.7, preferably 1:0.5; the poisoning agent B is dodecyl mercaptan, and the molar ratio of L-biopterin to dodecyl mercaptan is 1:0.2 to 1.0, preferably 1:0.53; the hydrogenation pressure is 1.0 atm; and the reaction temperature is 25°C.

[0032] In one embodiment, the metal catalyst reagent A in the catalytic reduction system is platinum dioxide (platinum black); the molar ratio of L-biopterin to platinum dioxide is 1:0.5 to 2.0, preferably 1:1.1; the poisoning agent B is quinoline, the molar ratio of L-biopterin to quinoline is 1:0.2 to 4.0, preferably 1:1; the hydrogenation pressure is 1.0 atm; and the reaction temperature is 25°C.

[0033] In one embodiment, the metal catalyst reagent A in the catalytic reduction system is Raney Ni; the molar ratio of L-biopterin to Raney Ni is 1:5 to 50, preferably 1:20; the poisoning agent B is pyridine, the molar ratio of L-biopterin to pyridine is 1:0.2 to 4.0, preferably 1:1; the hydrogenation pressure is 3.0 atm; and the reaction temperature is 50°C.

[0034] In one embodiment, the metal catalyst reagent A in the catalytic reduction system is 5% rhodium on carbon (Rh / C); the molar ratio of L-biopterin to 5% rhodium on carbon (Rh / C; based on the metal Rh content) is 1:0.1 to 1.0, preferably 1:0.8; the poisoning agent B is dimethyl sulfide, and the molar ratio of L-biopterin to dimethyl sulfide is 1:0.2 to 1.0, preferably 1:0.82; the hydrogenation pressure is 1.0 atm; and the reaction temperature is 25°C.

[0035] In one embodiment, the metal catalyst reagent A in the catalytic reduction system is 20% Pd(OH)2 / C; the molar ratio of L-biopterin to 20% Pd(OH)2 / C (calculated as Pd(OH)2) is 1:1.0 to 3.0, preferably 1:2.0; the poisoning agent B is copper acetate monohydrate, and the molar ratio of L-biopterin to copper acetate monohydrate is 1:0.2 to 4.0, preferably 1:1.0; the hydrogenation pressure is 1.0 atm; and the reaction temperature is 25°C.

[0036] Preferably, the preparative high-performance liquid chromatography (HPLC) purification conditions and steps for the crude product are as follows: Instrument: Shimadzu LC-20AP; Mobile phase A: 0.1% formic acid-water; Mobile phase B: acetonitrile; Flow rate: 50 mL / min; Detection wavelength: 220 nm; Column temperature: room temperature; Preparative column type: Hanbang DAC-50 dynamic axial compression column, column material: 316L stainless steel; Packing material: Huapu C18AQ-L, particle size 10 μm, pore size 100 Å; Injection volume: 50 mL; Gradient elution program is as follows:

[0037] Peaks with retention times of 10.2–11.5 min were collected, and the collected solutions were concentrated under reduced pressure. After the solvent was evaporated, the solutions were transferred to stainless steel freeze-drying trays and freeze-dried in a freeze dryer to obtain the target product.

[0038] Advantages of this invention:

[0039] This invention provides a method for preparing 7,8-dihydrobiopterin. The reagents used are all common and readily available. The method is simple to operate, has a high yield and strong selectivity, and yields a high-purity target product. It is suitable for the batch preparation of 7,8-dihydrobiopterin (BH2), providing sufficient samples for the preparation of sapropterin hydrochloride and for qualitative and quantitative analysis of impurities in research. Attached Figure Description

[0040] Figure 1 The PHPLC chromatogram of 7,8-dihydrobiopterin (BH2) was prepared for Example 2.

[0041] Figure 2 The HPLC chromatogram of 7,8-dihydrobiopterin (BH2) obtained in Example 2 is shown.

[0042] Figure 3 MS spectrum of 7,8-dihydrobiopterin (BH2). Detailed Implementation

[0043] The present invention will be further illustrated by the following embodiments. It should be understood that the embodiments of the present invention are merely for illustrating the present invention and are not intended to limit the present invention. Therefore, any simple improvements to the present invention under the premise of the method of the present invention are within the scope of protection claimed by the present invention.

[0044] The 7,8-dihydrobiopterin (BH2) sample obtained from the examples was identified as follows: a pale yellow solid. Elemental analysis results: C9H... 13N5O3: C, 45.19; H, 5.48; N, 29.27. Measured values ​​were C, 45.22; H, 5.61; N, 29.18. Specific rotation [ +34.71 。 ( c 0.4, 0.1 mol / L NaOH(aq)). MS ESI + : m / z 240.12 [M+H] + 262.11 [M+Na] + .

[0045] The high-performance liquid chromatography (HPLC) purity determination conditions for the obtained 7,8-dihydrobiophenin (BH2) were as follows: column: Waters Spherisorb SCX, 4.6 × 250 mm, 5 μm; detection wavelength: 220 nm; flow rate: 1.0 mL / min; column temperature: 25 ℃; mobile phase A: 25 mM sodium dihydrogen phosphate aqueous solution (adjusted to pH=2.5): methanol = 85:15; elution method: isocratic elution for 90 min; injection volume: 20 μL.

[0046] The following Examples 1-5 describe the preparative high-performance liquid chromatography (HPLC) purification conditions and steps: The preparative HPLC conditions are as follows: Instrument: Shimadzu LC-20AP; Mobile phase A: 0.1% formic acid-water; Mobile phase B: acetonitrile; Flow rate: 50 mL / min; Detection wavelength: 220 nm; Column temperature: room temperature; Preparative column type: Hanbang DAC-50 dynamic axial compression column, column material: 316L stainless steel; Packing material: Huapu C18AQ-L, particle size 10 μm, pore size 100 Å; Injection volume: 50 mL; Gradient elution program is as follows:

[0047] Peaks with retention times of 10.2–11.5 min were collected, and the collected solutions were concentrated under reduced pressure. After the solvent was evaporated, the solutions were transferred to stainless steel freeze-drying trays and freeze-dried in a freeze dryer to obtain the target product.

[0048] Example 1

[0049] L-Biopterin (2372.2 mg, 10 mmol) was added to 100 mL of 1 mol / L sodium hydroxide aqueous solution. After sonication and stirring to dissolve, 106.31 mg of 5% Pd / C (containing 0.05 mmol of Pd) and 10.73 mg (0.053 mmol) of dodecyl mercaptan were added. Under stirring, 4 mol / L hydrochloric acid aqueous solution was added to adjust the pH to 12. The air in the flask was replaced three times with hydrogen gas, and 1 atm H2 was introduced. The reaction was stirred at 25 °C for 6 h. After the reaction was confirmed to be complete, the catalyst was removed by filtration. 4 mol / L hydrochloric acid aqueous solution was added to adjust the pH to about 7. The filtrate was concentrated under reduced pressure at 40 °C to obtain the crude product. The solid was purified by preparative liquid chromatography to obtain 2230.65 mg of a pale yellow solid, with a yield of 93.24% and a purity of 99.95%.

[0050] Example 2

[0051] L-Biopterin (2372.2 mg, 10 mmol) was added to 100 mL of 1 mol / L sodium hydroxide aqueous solution. After sonication and stirring to dissolve, 24.98 mg of platinum dioxide (platinum black, 0.11 mmol) and 12.92 mg (0.1 mmol) of quinoline were added. Under stirring, 4 mol / L hydrochloric acid aqueous solution was added to adjust the pH to 12. The air in the flask was replaced three times with hydrogen gas, and 1 atm H2 was introduced. The reaction was stirred at 25 °C for 4 h. After the reaction was confirmed to be complete, the catalyst was removed by filtration. 4 mol / L hydrochloric acid aqueous solution was added to adjust the pH to about 7. The filtrate was concentrated under reduced pressure at 40 °C to obtain the crude product. The solid was purified by preparative liquid chromatography to obtain 2351.75 mg of a pale yellow solid, with a yield of 98.30% and a purity of 99.97%.

[0052] Example 3

[0053] L-Biopterin (2372.2 mg, 10 mmol) was added to 100 mL of tetrahydrofuran, dissolved by sonication and stirring, followed by the addition of 117.38 mg Raney Ni (2 mmol) and 7.91 mg pyridine (0.1 mmol). While stirring, sodium hydroxide aqueous solution was added to adjust the pH to 12. The air in the flask was replaced three times with hydrogen gas, and 3 atm H2 was introduced. The reaction was stirred at 50 °C for 6 h. After the reaction was confirmed to be complete, the catalyst was removed by filtration. 4 mol / L hydrochloric acid aqueous solution was added to adjust the pH to approximately 7. The filtrate was concentrated under reduced pressure at 40 °C to obtain the crude product. The solid was purified by preparative liquid chromatography to obtain 2120.89 mg of a pale yellow solid, with a yield of 88.65% and a purity of 99.85%.

[0054] Example 4

[0055] L-Biopterin (2372.2 mg, 10 mmol) was added to 100 mL of 1 mol / L sodium hydroxide aqueous solution. After sonication and stirring to dissolve, 164.66 mg of 5% Rh / C (containing 0.08 mmol of Rh) and 5.12 mg (0.0824 mmol) of dimethyl sulfide were added. Under stirring, 4 mol / L hydrochloric acid aqueous solution was added to adjust the pH to 12. The air in the flask was replaced three times with hydrogen gas, and 1 atm H2 was introduced. The reaction was stirred at room temperature for 5 h. After the reaction was confirmed to be complete, the catalyst was removed by filtration. 4 mol / L hydrochloric acid aqueous solution was added to adjust the pH to about 7. The filtrate was concentrated under reduced pressure at 40 °C to obtain the crude product. The solid was purified by preparative liquid chromatography to obtain 2272.63 mg of a pale yellow solid, with a yield of 95.00% and a purity of 99.74%.

[0056] Example 5

[0057] L-Biopterin (2372.2 mg, 10 mmol) was added to 100 mL of 75% ethanol aqueous solution, dissolved by sonication and stirring, and then 138.42 mg of 20% Pd(OH)₂ / C (0.2 mmol) and 18.16 mg (0.1 mmol) of copper acetate monohydrate were added. While stirring, sodium hydroxide aqueous solution was added to adjust the pH to 12. The air in the flask was replaced three times with hydrogen gas, and 1 atm H₂ was introduced. The reaction was stirred at room temperature for 3 h. After the reaction was confirmed to be complete, the catalyst was removed by filtration. 4 mol / L hydrochloric acid aqueous solution was added to adjust the pH to approximately 7. The filtrate was concentrated under reduced pressure at 40 °C to obtain the crude product. The solid was purified by preparative liquid chromatography to obtain 2318.46 mg of a pale yellow solid, with a yield of 96.91% and a purity of 99.57%.

[0058] Comparative Example 1

[0059] In a nitrogen glove box, 200 mg (0.85 mmol) L-biopterin and 600 mg (3.45 mmol) sodium dithionite were suspended in 6 mL of purified water and dissolved in 3 mol / L NaOH aqueous solution (pH≈10.5). The solution was heated to 70 °C, and the color changed from yellow to brown to pale yellow (10–20 min). After cooling to 0 °C and standing for 12 h, the pH dropped to approximately 6.5, and BH2 precipitated. The solution was filtered under exposed air and washed with a small amount of ice water and acetone. Recrystallization was performed in a nitrogen glove box with water (80 °C) and dried (40 °C / 0.01 Torr, 10 h) to give 139 mg (68.34%) of a pale yellow solid with a purity of 85.47%.

Claims

1. A method for preparing 7,8-dihydrobiopterin (BH2), characterized by, Starting with L-biopterin, a hydrogenation reaction was carried out under alkaline conditions in the presence of a catalytic reduction system to generate a product rich in BH2. The product was then purified by preparative high-performance liquid chromatography (HPLC) to obtain high-purity 7,8-dihydrobiopterin (BH2). The route is as follows: 。 2. The method according to claim 1, characterized in that, Specifically, the steps include the following: L-Biopterin was added to solvent C and stirred until completely dissolved. Then, the catalytic reduction system reagent was added, and the pH of the reaction system was adjusted to 10–12. The mixture was transferred to a hydrogenation reactor, purged with nitrogen or argon, and hydrogen gas was introduced at a certain pressure. The reaction was kept at a certain temperature until it was confirmed to be complete. The catalyst was removed by filtration, and acid D was added to adjust the pH to 6.5–7.

5. The mixture was concentrated to dryness to obtain a mixed solid containing the target compound that had not been separated. The solid was purified by preparative high-performance liquid chromatography to obtain a pale yellow solid final product, 7,8-dihydrobiopterin (BH2).

3. The method according to claim 2, characterized in that, The catalytic reduction system reagent is composed of a metal catalyst reagent A and a poisoning agent reagent B; the metal catalyst reagent A is selected from one or more of palladium on carbon (Pd / C), platinum dioxide (platinum black), Raney Ni, rhodium on carbon (Rh / C), and palladium hydroxide on carbon (Pd(OH)2 / C); the poisoning agent reagent B is selected from one or more of thiols, disulfides, quinolines, pyridines, amines, lead salts, and copper salts.

4. The method according to claim 3, characterized in that, The catalytic reduction system reagents are palladium on carbon (Pd / C) / thiol reagent combination, platinum dioxide (platinum black) / quinoline reagent combination, Raney Ni / pyridine / amine reagent combination, rhodium on carbon (Rh / C) / disulfide reagent combination, and palladium hydroxide on carbon (Pd(OH)2 / C) / lead salt or copper salt reagent combination.

5. The method according to claim 4, characterized in that, The thiol in the catalytic reduction system is one of dodecanethiol, octylthiol, or benzylthiol; the disulfide is one of dimethyl disulfide or diphenyl disulfide; the quinoline is one of quinoline or isoquinoline; the pyridine reagent is pyridine; the amine reagent is one of triethylamine or ethylenediamine; the lead salt is lead acetate; and the copper salt is copper acetate monohydrate.

6. The method according to claim 2, characterized in that, The solvent C mentioned in the step is selected from one or more of water, methanol, ethanol, isopropanol, 50% methanol aqueous solution, 75% ethanol aqueous solution, 95% ethanol aqueous solution, tetrahydrofuran, 1 mol / L sodium hydroxide aqueous solution, 0.1 mol / L sodium hydroxide aqueous solution, and DMSO; more preferably, it is a 1 mol / L sodium hydroxide aqueous solution.

7. The method according to claim 2, characterized in that, The heat preservation reaction temperature mentioned in the steps is 10-50℃.

8. The method according to claim 2, characterized in that, The hydrogenation pressure mentioned in the steps is 0.5 to 4.0 atm.

9. The method according to claim 2, characterized in that, The preparative high-performance liquid chromatography (HPLC) purification conditions and steps were as follows: Instrument: Shimadzu LC-20AP; Mobile phase A: 0.1% formic acid-water; Mobile phase B: acetonitrile; Flow rate: 50 mL / min; Detection wavelength: 220 nm; Column temperature: room temperature; Preparative column type: Hanbang DAC-50 dynamic axial compression column, column material: 316L stainless steel; Packing material: Huapu C18AQ-L, particle size 10 μm, pore size 100 Å; Injection volume: 50 mL; Gradient elution program: ， Peaks with retention times of 10.2–11.5 min were collected, and the collected solutions were concentrated under reduced pressure. After the solvent was evaporated, the solutions were transferred to stainless steel freeze-drying trays and freeze-dried in a freeze dryer to obtain the target product.

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