CN114560876A

CN114560876A - Ruidexiwei related substance and preparation method thereof

Info

Publication number: CN114560876A
Application number: CN202210089721.9A
Authority: CN
Inventors: 何匡; 何人宝; 孔佳辉; 史博峰; 陈豪; 夏海建
Original assignee: Zhejiang Yongtai Pharmaceutical Co ltd; ZHEJIANG YONGTAI TECHNOLOGY CO LTD
Current assignee: Zhejiang Yongtai Pharmaceutical Co ltd; ZHEJIANG YONGTAI TECHNOLOGY CO LTD
Priority date: 2021-01-26
Filing date: 2022-01-25
Publication date: 2022-05-31
Also published as: CN112920203A

Abstract

The invention provides a Rudexilevir related substance I and a preparation method thereof, wherein the method takes iodo-triazine and nucleoside as raw materials, and specifically comprises the following steps: adding iodotriazine into an organic solvent, cooling to-10-30 ℃, adding trimethylchlorosilane, and stirring for 10-30min under heat preservation; cooling to-30-20 deg.C, adding phenylmagnesium chloride, stirring for 30-60 min; adding isopropyl magnesium chloride-lithium chloride, and stirring for 30-60min under heat preservation; adding organic solvent solution of nucleoside, stirring for 30-60 min; adding acid water, extracting with organic solvent, concentrating to obtain crude product of related substance I, and refining to obtain pure product of related substance I. The preparation method has the advantages of easily available raw materials, mild reaction conditions, high safety coefficient and high purity of the obtained related substance I. And the method has strong operability and is easy to operate in a laboratory.

Description

Ruidexiwei related substance and preparation method thereof

Technical Field

The invention belongs to the field of organic synthetic pharmaceutical chemistry, and particularly relates to a Rudexilvir related substance I and a preparation method thereof.

Background

In the process of drug production, impurity research is an indispensable and very important part, and the residual impurities of drug intermediates can bring potential risks to the drug finished products in the later period. The presence of these impurities not only affects the efficacy of the drug, but also causes problems during production and storage, and some impurities may even cause toxic side effects. Therefore, the analysis and research on the medicine impurities can ensure the safety, effectiveness and stability of the medicine application and provide a basis for the quality assurance of the production and circulation processes. The impurity standard substance is a standard substance for identifying, checking and measuring the content of impurities. Therefore, it is very necessary to prepare and study impurity standards during the production and quality control processes.

Reidesciclovir belongs to the class of nucleoside analogs, is an RNA-dependent RNA polymerase (RdRp) inhibitor, and can be used to combat viruses by inhibiting viral nucleic acid synthesis. Current clinical studies on ebola virus infection have progressed to phase II. Mice infected with MERS performed much better with this combination therapy, reduced viral replication and improved lung function. Recent research shows that the Redexilvir has a certain activity effect on inhibiting the new coronavirus.

The Reidesciclovir synthesis method disclosed in patent CN105343098A by Gilidex corporation is characterized in that iodo-aminotriazine and nucleoside lactone are used as starting materials, iodo-triazine and nucleoside are in butt joint to form a key intermediate P3, and further cyano substitution and other series of conversions are carried out to generate Reidesciclovir.

In the detection of the bulk drug of the Reidesciclovir, the inventor finds that an unknown impurity exists, and the peak area ratio of the unknown impurity is generally 0.05-0.10%. The impurity is a Reidesciclovir related substance I, namely (2R,3R,4R) -1, 1-di (4-aminopyrrolo [2, 1-f) through high resolution mass spectrum and nuclear magnetic resonance characterization][1,2,4]Triazin-7-yl) -2,3, 5-tribenzyloxypentane-1, 4-diol having the following structure:

in the process of development of a Reidesciclovir analysis method and subsequent finished product inspection, the impurities in the Reidesciclovir are required to be positioned and quantitatively researched by using the standard products of the impurities, so that a large amount of standard products of the Reidesciclovir impurity I are required to be used. For the preparation of the ridciclovir-related substance I, a conventional impurity separation method can be adopted: target impurities are separated from a Redexiluwei bulk drug sample, but the content of the target impurities can only reach 0.11% at most through HPLC (high performance liquid chromatography) detection, and the sample also contains a plurality of similar impurities with similar contents, which can interfere separation, the separation period is long, a pure product can be obtained through multiple times of separation, and the total yield is generally about 0.03%.

Based on the above, the application provides a Rudeciclovir related substance I and a preparation method thereof.

Disclosure of Invention

The invention aims to provide a preparation method of a Rudexilvir related substance I, namely (2R,3R,4R) -1, 1-bis (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -2,3, 5-tribenzyloxypentane-1, 4-diol, which is used for researching impurity standards.

In order to achieve the purpose, the invention adopts the following technical scheme:

the related substance I of the Reidesciclovir is (2R,3R,4R) -1, 1-di (4-aminopyrrolo [2, 1-f)][1,2,4]Triazin-7-yl) -2,3, 5-tribenzyloxypentane-1, 4-diol having the formula:

the preparation method of the Reidesciclovir related substance I comprises the following steps:

(1) adding iodotriazine (P1) into an organic solvent, cooling to-10-30 ℃, adding trimethylchlorosilane, and stirring for 10-30min under heat preservation;

(2) cooling to-30-20 deg.C, adding phenylmagnesium chloride, stirring for 30-60 min;

(3) adding isopropyl magnesium chloride-lithium chloride, and stirring for 30-60min under heat preservation;

(4) adding organic solvent solution of nucleoside (P2), keeping temperature and stirring for 30-60 min;

(5) adding acid water, extracting with organic solvent, concentrating to obtain crude product of related substance I, and refining to obtain pure product of related substance I.

The structure of iodo-triazine (P1) in the invention is as follows:

the structure of the nucleoside (P2) is:

preferably, the organic solvent in step (1) and step (4) is selected from one or more of ethyl acetate, acetonitrile, toluene, xylene, dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-ether, dimethylformamide, chloroform, isopropyl acetate; further preferred is tetrahydrofuran; the volume mass ratio of the organic solvent to the iodotriazine is 5-20: 1; further preferably 10-15: 1.

Preferably, the molar ratio of trimethylchlorosilane to iodotriazine in step (1) is 1.0-2.5:1, more preferably 2.0-2.2: 1. The reaction temperature is more preferably 0 to 5 ℃.

Preferably, the molar ratio of phenylmagnesium chloride to iodotriazine in step (2) is 1.5-2.5:1, more preferably 2.0-2.2: 1. The reaction temperature is preferably-5 to 0 ℃.

Preferably, the molar ratio of isopropyl magnesium chloride-lithium chloride to iodotriazine in step (3) is 0.5 to 1.2:1, and more preferably 0.9 to 1.0: 1. The reaction temperature is preferably-5 to 0 ℃.

Preferably, the molar ratio of nucleoside to iodotriazine in step (4) is 0.3-1.5:1, more preferably 0.4-0.6: 1. The reaction temperature is preferably-5 to 0 ℃.

Preferably, the acid in step (5) is selected from an organic acid, an inorganic acid, or a combination thereof; the organic acid is selected from one or more of formic acid, acetic acid, trifluoroacetic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid and p-toluenesulfonic acid; the inorganic acid is selected from one or more of hydrochloric acid, sulfuric acid and phosphoric acid.

Preferably, the organic solvent in step (5) is one or more selected from ethyl acetate, toluene, xylene, dichloromethane, methyl tert-ether, chloroform and isopropyl acetate; further preferred is ethyl acetate or dichloromethane.

The refining specifically comprises the following steps: adding solvent 4-10 times of the mass of the crude product of the related substance I, heating to 50-70 ℃, slowly cooling to 0-20 ℃, and filtering to obtain a pure product.

Preferably, the solvent used in the refining process in the step (5) is one or more selected from ethyl acetate, toluene, xylene, methyl tert-ether, isopropyl acetate, n-hexane, n-heptane, cyclohexane and petroleum ether; more preferred is methyl tertiary ether.

Compared with the prior art, the invention has the following beneficial effects:

1) the method provided by the application is adopted to prepare the Reidesciclovir related substance I, the yield of the Reidesciclovir related substance I can reach 60-80%, the yield is greatly improved, and the quality is good; compared with the traditional method, the yield can be improved by more than one thousand times.

2) According to the method provided by the application, the adopted solvent can be tetrahydrofuran, dichloromethane, ethyl acetate, methyl tertiary ether and other organic solvents, and an unusual or expensive organic solvent is not involved, so that the chiral center of the product is stable under an acidic condition, and isomerization cannot occur.

3) In the whole preparation process, the used reagents are safe and environment-friendly, the reaction conditions are mild, special equipment and raw materials are not needed, the preparation period is short, the treatment is simple, the operation is easy, and the cost is low.

4) The related substance I obtained by the invention can be used as an important index in quality control of the Reidesciclovir, the intermediate thereof or the preparation thereof, and has the advantages of simple preparation method and environmental friendliness.

5) The invention ensures that the content of the impurity I in the Reidesciclovir is less than 0.10 percent by controlling the content of the impurity in the compound P3 as described in claim 1 to be less than 0.50 percent, thereby meeting the control requirement of a single impurity.

Drawings

Figure 1 is a liquid phase detection diagram of a reidesavir bulk drug substance produced by the process of example 1;

figure 2 is a liquid quality inspection chart of a ridciclovir bulk drug produced by the process of example 1;

FIG. 3 is a liquid phase diagram of related substance I in a bulk drug substance of Reidesciclovir produced by the process of example 1;

FIG. 4 is a liquid mass spectrum of related substance I in a bulk drug substance of Reidesciclovir produced by the process of example 1;

FIG. 5 is nuclear magnetic hydrogen spectrum of substance I prepared by the present invention;

FIG. 6 is a carbon spectrum of a substance I prepared according to the present invention;

FIG. 7 is a numbering scheme of Reidesciclovir related substance I prepared by the invention;

FIG. 8 is a heavy water exchange hydrogen spectrum of related substance I prepared by the present invention;

FIG. 9 is a numbering scheme of heavy water exchange of related substance I prepared according to the present invention.

Detailed Description

The present invention will be further explained with reference to specific examples in order to make the technical means, the technical features, the technical objectives and the effects of the present invention easier to understand, but the following examples are only preferred embodiments of the present invention, and not all embodiments of the present invention. Other embodiments obtained by persons skilled in the art without making creative efforts based on the embodiments in the implementation belong to the protection scope of the invention.

The experimental methods in the following examples are conventional methods unless otherwise specified, and materials, reagents and the like used in the following examples are commercially available unless otherwise specified. Wherein iodotriazine (P1), nucleoside (P2), Tetrahydrofuran (THF), trimethylchlorosilane (TMSCl), phenylmagnesium chloride in tetrahydrofuran (PhMgCl), isopropylmagnesium chloride in lithium chloride in tetrahydrofuran (i-PrMgCl. LiCl) are available from Michelin reagent. The manufacturer of the instrument used in the examples described below was Taizhou Xinli instruments, and the manufacturer of the detection instrument was Agilent.

Example 1

In the detection of the bulk drug of the Reidesciclovir, the applicant finds that an unknown impurity exists.

The route diagram for producing the bulk drug of the Reidesciclovir is as follows:

the inclusion of Reidesciclovir in the product prepared by the above procedure is demonstrated by liquid phase detection (FIG. 1) and liquid quality detection (FIG. 2). A liquid phase spectrum (figure 3) and a liquid mass spectrum (figure 4) prove that an impurity peak corresponding to 15min in the preparation process is related to a substance I, and the peak area ratio is generally 0.05-0.10%. The impurity is identified as a Reidesciclovir related substance I, namely (2R,3R,4R) -1, 1-bis (4-aminopyrrolo [2,1-f ] [1,2,4] triazin-7-yl) -2,3, 5-tribenzyloxypentane-1, 4-diol, which has the following structure through high resolution mass spectrum and nuclear magnetic resonance characterization:

example 2

The preparation method of the Reidesciclovir related substance I comprises the following synthetic process:

the method specifically comprises the following steps:

(1)130g of the substrate P1(0.5mol) are dissolved in 1300mL of THF and cooled to 5 ℃. 108g of TMSCl is slowly added, the temperature is kept and the stirring is carried out for 0.5h, and the temperature is reduced to 0 ℃.

(2) 525mL of PhMgCl (2M in THF) is slowly dropped into the reactor, the internal temperature is controlled to be-5-0 ℃, the temperature is kept and the stirring is carried out for 0.5h after the addition is finished, and the temperature is cooled to-5 ℃. (Note: PhMgCl in a molar amount of 0.525X 2. about.1.05 mol)

(3) 330mL of i-PrMgCl. LiCl (1.5M in THF) was added dropwise, the internal temperature was controlled at-5 to 0 ℃ and the temperature was kept for 40min after the addition.

(4) A solution of P2(105g) in THF (200mL) was added dropwise thereto, the internal temperature was controlled at-5-0 ℃ and the temperature was kept for 1 hour after the addition.

(5) Dropwise adding dilute hydrochloric acid for quenching, adjusting the pH to 5-6, adding 1000mL ethyl acetate for extraction, and concentrating an organic phase to obtain a crude product; adding methyl tertiary ether solvent with the mass 6 times of that of the crude product into the crude product of the related substance I, heating to 60 ℃, keeping for 1-2h, slowly cooling to 10 ℃, keeping for 1-2h, and filtering to obtain 137g of a pure product, wherein the yield is 80%, and the purity is 99.2%.

Example 3: 1.2 molar ratio (0.6mol) of phenylmagnesium chloride

The only difference from example 1 is that: the amount of PhMgCl added in step (2) was 300mL, and the other steps and experimental parameters were the same as those in example 1. The product was purified to obtain 127g of pure product, 74% yield and 98.6% purity.

Example 4: 1.2 molar ratio (0.6mol) of trimethylchlorosilane

The only difference from example 1 is that: the amount of TMSCl added in step (1) was 129.6g, and the other steps and experimental parameters were the same as those in example 1. The product was purified to obtain 121g of a pure product with a yield of 71% and a purity of 97.8%.

Example 5: 1.0 molar ratio (0.5mol) of nucleosides

The only difference from example 1 is that: step (4) 209g of P2 in THF (200mL) was added dropwise, and the other steps and experimental parameters were the same as in example 1. The product was purified to obtain 111g of pure product with a yield of 65% and a purity of 98.4%.

Example 6

The only difference from example 1 is that: the temperature in step (2) was set to 10 ℃ and the other steps and experimental parameters were the same as in example 1. The product was purified to obtain 113g of pure product, yield 66% and purity 95.8%.

Comparative example 1

The only difference from example 1 is: the temperature in step (1) was set at-20 ℃ and the other steps and experimental parameters were the same as in example 1. The product was purified to give 96g of a pure product, 56% yield and 93.5% purity.

Comparative example 2

The only difference from example 1 is that: the stirring time in step (1) was set to 5min, and the other steps and experimental parameters were the same as in example 1. The crude product was purified to give 79g of a pure product in 46% yield and 92.8% purity.

Comparative example 3

The only difference from example 1 is that: the temperature in step (2) was set to 30 ℃ and the other steps and experimental parameters were the same as in example 1. The product was purified to obtain 84g of a pure product with a yield of 49% and a purity of 91.8%.

Comparative example 4

The only difference from example 1 is that: the stirring time in step (2) was set to 20min, and the other steps and experimental parameters were the same as in example 1. The product was purified to obtain 87g of a pure product with a yield of 51% and a purity of 93.6%.

Comparative example 5

The only difference from example 1 is that: the temperature in step (3) was set to 40 ℃ and the other steps and experimental parameters were the same as in example 1. The product was purified to obtain 72g of pure product, yield 42% and purity 92.3%.

Test example

The structural representation of the liquid mass and the nuclear magnetic resonance structure of the prepared Reidesciclovir related substance I confirms that the structure of a synthetic product is correct, and the liquid mass (figure 4), the nuclear magnetic resonance hydrogen spectrum (figure 5) and the carbon spectrum (figure 6) are analyzed. The molecular formula of the related substance I is as follows: C38H38N8O5, the calculated molecular weight is 686.30, in FIG. 4, the anion peak is [ M-H ]:685.10, and the cation peak is [ M + H ]:687.41, which is in accordance with the theoretical calculation. The compound numbers are shown in FIG. 7.

TABLE 1 Nuclear magnetic analysis of Reidesciclovir-related substance I

Proton type	Chemical shift	Home H encoding	Number of protons
				O-H	3.4ppm,5.0ppm	H-9,5	2H
C-H	3.5-5.0ppm,5.5ppm	H-6,7,8,10,11,12,13	11H
				C-H	6.5-7.5ppm	H-(Ph1,2,3),3,3’,4,4’	19H
C-H	7.7ppm,7.8ppm	H-2,2’	2H
				N-H	7.7-8.0ppm	H-1,1’	4H

Note: the chemical shifts of O-H and N-H disappeared after heavy water exchange, as shown in FIGS. 8 and 9.

TABLE 2 Nuclear magnetic analysis of Reidesciclovir-related substance I

Proton type	Chemical shift	Home H encoding	Number of protons
				C	70-90ppm	C-7,8,10,11,12,13,14	7C
C	100-120ppm	C-3,3’,4,4’,5,5’	6C
				C	130-160ppm	C-(Ph1,2,3),1,1’,2,2’,6,6’	24C

Characterization of the use of Reidesciclovir-related substance I

Quality control for Reidesciclovir

P3 with contents of impurities I of the Reidsievir of 0.10%, 0.30%, 0.50%, 0.70% and 0.90% was obtained by weighing P3 (standard product with purity of more than 99.5% and not containing impurities I of the Reidsievir) and impurities I of the Reidsievir (from example 2) in different masses and mixing them uniformly. The method comprises the following steps:

table 3.

After weighing, P3 and the impurity I of the Rudeseivir are uniformly mixed to obtain P3 with the content of the impurity I of the Rudeseivir of 0.10%, 0.30%, 0.50%, 0.70% and 0.90%.

The specific experimental procedure for preparing ridciclovir using P3 with 0.10% of the ridciclovir impurity I is as follows:

preparation of P4:

dissolving 10g P3 in 300g DCM, cooling to-35 ℃, adding 6g TfOH, adding 10g TMSOTf after 10min, stirring for 30min under heat preservation, cooling to-45 ℃, adding 6g TMSCN, stirring for 1h under heat preservation, detecting that the raw material is less than 1% by controlling, adding 13g TEA for quenching, slowly pouring the reaction solution into sodium carbonate aqueous solution, extracting, and separating liquid. Concentrating the organic phase, thermally pulping the crude product with n-hexane, cooling to 0-5 ℃, and performing suction filtration. 8.52g of P4 were obtained in 84% yield.

Preparation of P5:

8g P4 was dissolved in 50g of DCM, cooled to below-25 ℃ and 80g of BCl was added₃Stirring the obtained DCM solution (1M) for 2 hours under heat preservation, cooling to below-25 ℃, adding 20g of methanol for quenching, heating to room temperature, evaporating to remove DCM, adjusting the pH value to about 6-7 by using a potassium carbonate aqueous solution, pulping, filtering by suction, and drying to obtain the product. 3.2g of product is obtained with a yield of 80%.

Preparation of P6:

3.0g of substrate was added with 30mL of acetone, 3.6g of methanol acetonide, and 1g of concentrated sulfuric acid, stirred at room temperature for 20min, then heated to 65 ℃ and stirred for 1-2 h. Cooling to 0-10 deg.C, adding sodium carbonate solution to quench reaction, distilling off acetone, adding 20g water, 20gEA, extracting, separating liquid, and concentrating organic phase to obtain P6 oily substance 3.2g with 88% yield.

Preparation of P8:

3.2g P6 is dissolved in 30mL acetonitrile, 4.5g P7 and 1g anhydrous magnesium chloride are added, the temperature is raised to 50 ℃ and stirred for 30min, 5g DIPEA is added, the temperature is kept and stirred for 1-2h, the temperature is lowered to 20 ℃, 50mL EA is used for dilution, an appropriate amount of 5% citric acid aqueous solution is added, the pH is adjusted to be neutral, extraction liquid separation is carried out, an organic phase is washed with water, dried by anhydrous sodium sulfate and concentrated, and 5.8g P8 is obtained. The yield thereof was found to be 93%.

Preparation of Reidesciclovir:

5.8g P8 is dissolved in 50mL THF, cooled to 0 ℃, 10g concentrated hydrochloric acid is slowly added, the temperature is raised to 15 ℃, stirred for 5h, cooled to 0 ℃, potassium carbonate aqueous solution is slowly added, the pH is adjusted to about 8, 50g EA and 50g water are extracted and separated, an organic phase is washed by water and concentrated, 10g ethanol is dissolved, 40g drinking water is added dropwise for crystallization, 4.6g of Reidesvir is obtained, and the yield is 85%.

The purity of the impurity I in the prepared Redexilvir sample is 0.03% through HPLC detection.

The preparation method of the Reidesciclovir comprises the steps of preparing the Reidesciclovir by using P3 containing 0.30%, 0.50%, 0.70% and 0.90% of Reidesciclovir impurity I through the processes, wherein the purities of the impurity I in the Reidesciclovir are respectively 0.06%, 0.09%, 0.12% and 0.15%.

The contents of the impurity I of the Rudeseivir in P3 are different, and the results of the Rudeseivir prepared by P3 containing the impurity I are as follows:

table 4.

And (4) conclusion: the single impurity in each large pharmacopoeia related substance is generally required to be less than 0.10 percent. When the content of the impurity I in the P3 is 0.50%, the impurity I in the Reidesciclovir is generated by the impurity in a series of synthesis steps P3, the impurity I is an index of 0.09% close to 0.10%, the content of the impurity in the P3 is strictly controlled to be less than 0.50%, and the impurity I in the Reidesciclovir can be ensured to meet the requirement of quality standard.

Finally, it should be noted that the above-mentioned contents are only used for illustrating the technical solutions of the present invention, and not for limiting the protection scope of the present invention, and that the simple modifications or equivalent substitutions of the technical solutions of the present invention by those of ordinary skill in the art can be made without departing from the spirit and scope of the technical solutions of the present invention.

Claims

1. The Reidcciclovir related substance I is characterized in that the related substance I is (2R,3R,4R) -1, 1-bis (4-aminopyrrolo [2, 1-f)][1,2,4]Triazin-7-yl) -2,3, 5-tribenzyloxypentane-1, 4-diol having the formula:

2. a process for the preparation of ridciclovir-related substance I according to claim 1, comprising the steps of:

(1) adding iodotriazine into an organic solvent, cooling to-10-30 ℃, adding trimethylchlorosilane, and stirring for 10-30min under heat preservation;

(4) adding organic solvent solution of nucleoside, stirring for 30-60 min;

3. A preparation method of ridciclovir related substance I according to claim 2, characterized in that the organic solvent in step (1) and step (4) is selected from one or more of ethyl acetate, acetonitrile, toluene, xylene, dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-ether, dimethylformamide, chloroform, isopropyl acetate; the volume mass ratio of the organic solvent to the iodotriazine is 5-20: 1.

4. A process for preparing ridciclovir related substance I according to claim 2, wherein the molar ratio of trimethylchlorosilane to iodotriazine in step (1) is 1.0-2.5: 1.

5. A process for preparing ridciclovir-related substance I according to claim 2, wherein the molar ratio of phenylmagnesium chloride to iodotriazine in step (2) is 1.5-2.5: 1.

6. A process for preparing ridciclovir-related substance I according to claim 2, wherein the molar ratio of isopropyl magnesium chloride-lithium chloride to iodotriazine in step (3) is 0.5-1.2: 1.

7. A process for preparing ridciclovir-related substance I according to claim 2, wherein the molar ratio of nucleoside to iodotriazine in step (4) is 0.3-1.5: 1.

8. A process for the preparation of ridciclovir related substance I according to claim 2, wherein in step (5) the acid is selected from organic acid, inorganic acid or combination thereof; preferably, the organic acid is selected from one or more of formic acid, acetic acid, trifluoroacetic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid and p-toluenesulfonic acid; the inorganic acid is selected from one or more of hydrochloric acid, sulfuric acid and phosphoric acid.

9. A preparation method of ridciclovir related substance I according to claim 2, wherein the organic solvent in step (5) is one or more selected from ethyl acetate, toluene, xylene, dichloromethane, methyl tert-ether, chloroform and isopropyl acetate.

10. A quality control method of Reidesciclovir is characterized by comprising the following steps: controlling the content of the impurity of claim 1 in a compound P3 to be less than 0.50 percent, and enabling the content of the impurity I in the Reidcciclovir to be less than 0.10 percent, wherein the compound P3 is