Intermediate compound of pilocarpine and preparation method thereof
Patent Information
- Application Number
- CN202480025334.6
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Priority Date
- 2023-04-14
- Filing Date
- 2024-04-11
- Publication Date
- 2025-11-11
AI Technical Summary
The existing pilocarpine synthesis method has a long route, uses dangerous or expensive sodium metal and precious metals, and has low enzymatic hydrolysis and separation efficiency, resulting in high industrial production costs and inconvenience.
A new intermediate compound preparation method is adopted, including the reaction of compound II with a halogenated reagent, oxidant treatment, azide reagent reaction, followed by reduction, methyl isothiocyanate reaction and oxidative desulfurization steps. The reaction conditions are mild and the operation is simple. , the target product purity is as high as 99.9%.
The efficient and simple preparation of pilocarpine is achieved, which is suitable for industrial production, reduces costs, avoids the use of dangerous materials and expensive enzyme hydrolysis, and improves the purity and yield of the product.
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Abstract
Description
Intermediate compound of pilocarpine and preparation method thereof Technical Field
[0001] The present invention relates to the field of medicinal chemistry, and more particularly to intermediate compounds for synthesizing pilocarpine and methods for preparing the intermediate compounds. Background Art
[0002] Glaucoma is an eye disease characterized by intermittent or persistent increases in intraocular pressure. Sustained high intraocular pressure can damage various eye structures and visual function. If left untreated, it can lead to complete loss of vision and even blindness.
[0003] Pilocarpine, also known as pilocarpine, is an alkaloid extracted from the leaves of Pilocarpus microphyllus Stapf and Pilocarpus microphyllus Stapf, which has the effect of simulating acetylcholine.
[0004] Pilocarpine can be used to treat primary glaucoma, including both open-angle and angle-closure glaucoma. Compared to physostigmine, pilocarpine has a milder, shorter-lived effect and a more stable aqueous solution. It is also used for salivary gland hypofunction; its oral tablet, SALAGEN, can relieve dry mouth. It can also be used for miosis during cataract surgery and for the symptomatic treatment of atropine-related drug poisoning. Currently, medicinal pilocarpine is isolated and extracted from plants, but with increasing environmental protection requirements, plant extraction is becoming increasingly difficult. Furthermore, currently known methods for obtaining pilocarpine through chemical synthesis still face many difficulties.
[0005] According to Tetrahedron, 1972, 28, 967-972, patent applications JP03161481, and US Pat. No. 5,182,198, the current synthesis of pilocarpine is not only long but also involves the use of hazardous or expensive materials such as metallic sodium and precious metal rhodium. Furthermore, two enzymatic hydrolysis steps are required. However, the enzymes are expensive, require large amounts, and have low hydrolysis yields. These factors greatly inconvenience industrial production and significantly increase production costs.
[0006] Therefore, how to prepare pilocarpine simply and efficiently becomes the key to the industrialization of pilocarpine.
[0007] Summary of the Invention
[0008] The present invention aims to overcome the deficiencies of the prior art by providing a novel method for preparing a pilocarpine intermediate, a compound of formula I, and its use in the preparation of pilocarpine. This method has the advantages of mild reaction conditions, a simple reaction process, convenient operation, a high total yield of the target product, and a purity of up to 99.9%, making it particularly suitable for industrial production.
[0009] In a first aspect, the present invention provides a method for preparing a compound of formula V, comprising the following steps:
[0010] Step 1: reacting the compound of formula II with a halogenating agent and then hydrolyzing to obtain a compound of formula III;
[0011] Step 2: reacting the compound of formula III with an oxidizing agent to obtain a compound of formula IV;
[0012] Step 3: reacting the compound of formula IV with an azidating agent to obtain a compound of formula V;
[0013] Wherein, R is H or ethyl; X is halogen selected from Cl, Br or I.
[0014] In one embodiment, the halogenating agent in step 1 is selected from one of chlorine, NCS, trichloroisocyanuric acid, dichlorohydantoin, lithium chloride, sodium chloride, potassium chloride, tetrabutylammonium chloride, bromine, NBS, dibromohydantoin, tribromoisocyanuric acid, lithium bromide, sodium bromide, potassium bromide, tetrabutylammonium bromide, iodine, diiodohydantoin, lithium iodide, sodium iodide, potassium iodide and tetrabutylammonium iodide, or a combination of two or more of these halogenating agents.
[0015] In one embodiment, the reaction solvent in step 1 is selected from toluene, tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile, dichloromethane, chloroform, methyl tert-butyl ether, ethyl acetate, hexane, n-heptane, acetone, or a combination of two or more reaction solvents.
[0016] In one embodiment, the oxidant in step 2 is selected from one of Dess-Martin periodinane, hydrogen peroxide, Jones reagent, PCC, PDC and Swern reagent, or a combination of two or more of these oxidants.
[0017] In one embodiment, the azidation reagent in step 3 is selected from one of sodium azide, trimethylsilyl azide, diphenylphosphoryl azide, tributyltin azide, tetrabutylammonium azide, tetramethylguanidine azide and ethyl azidoacetate, or a combination of two or more of these azidation reagents.
[0018] In one embodiment, the reaction solvent in step 2 and step 3 is selected from one of toluene, tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile, dichloromethane, chloroform, methyl tert-butyl ether, ethyl acetate, hexane, n-heptane, acetone, or a combination of two or more reaction solvents.
[0019] In a second aspect, the present invention provides a method for preparing a compound of formula I, comprising the following steps:
[0020] Step 4: Reducing the compound of formula V with a reducing agent to obtain a compound of formula VI;
[0021] Step 5: reacting the compound of formula VI with methyl isothiocyanate to obtain a compound of formula VII or a salt thereof;
[0022] Step 6: Oxidative desulfurization of the compound of formula VII to obtain a compound of formula I;
[0023] Wherein, R is H or ethyl.
[0024] In one embodiment, the reduction reaction in step 4 is a catalytic hydrogenation reduction reaction or a reduction reaction using a reducing agent, wherein the catalytic hydrogenation reduction reaction uses a combination of a catalyst and a reducing agent, the catalyst is selected from Ni, Pd / C, Pt / C, PtO2, palladium barium sulfate or any combination thereof, and the reducing agent is selected from hydrogen, ammonium chloride, formic acid and ammonium formate or any combination thereof; the reducing agent used in the reduction reaction using a reducing agent is selected from one of sodium borohydride, lithium borohydride, sodium cyanoborohydride, potassium borohydride, borane, red aluminum and lithium aluminum hydride, or a combination of two or more of the reducing agents.
[0025] In one embodiment, the salt in step 5 is selected from hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate or nitrate.
[0026] In one embodiment, the oxidizing agent in step 6 is selected from hydrogen peroxide, Jones reagent or sodium nitrite.
[0027] In one embodiment, the reaction solvent in step 4, step 5 and step 6 is selected from one of methanol, ethanol, isopropanol, toluene, tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile, dichloromethane, chloroform, methyl tert-butyl ether, ethyl acetate, hexane, n-heptane, and acetone, or a combination of two or more thereof.
[0028] In a third aspect, the present invention provides a method for preparing pilocarpine or its hydrochloride or nitrate.
[0029] When R in the compound of formula I is ethyl, it is called the compound of formula I'. The method comprises the steps of crystallizing the compound of formula I' into a salt to obtain pilocarpine hydrochloride or nitrate:
[0030] In one embodiment, the compound of formula I' is dissolved in an alcohol reagent, and hydrochloric acid or nitric acid is added for recrystallization to obtain pilocarpine hydrochloride or nitrate.
[0031] The alcohol solvent is selected from, for example, methanol, ethanol, n-propanol, isopropanol, n-butanol, or any combination thereof.
[0032] When R is H in the compound of formula I, it is called a compound of formula I", and the method comprises the steps of reacting the compound of formula I" with a halogenating agent CH3CH2X to obtain a compound of formula I' wherein R is ethyl, and then crystallizing the salt to obtain pilocarpine hydrochloride or nitrate:
[0033] In a specific embodiment, the compound of formula I' is dissolved in an organic solvent, and a strong base is added at -10 to 5°C. After the addition is complete, the mixture is stirred at this temperature for 0.5-1.5 hours. Ethyl bromide is added dropwise, and then the temperature is raised to 15-25°C. The reaction is stirred for 2.0-3.0 hours. Hydrochloric acid or ammonium chloride solution is added to quench the reaction, and the mixture is washed, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to obtain a compound of formula I'.
[0034] The organic solvent is selected from, for example, toluene, acetonitrile, isopropyl acetate, diethyl ether, isopropyl ether, methyl tert-butyl ether, tetrahydrofuran, methyltetrahydrofuran, and 1,4-dioxane.
[0035] The strong base is selected from, for example, lithium hexamethyldisilazide, sodium hexamethyldisilazide or LDA.
[0036] The methods of the first, second and third aspects of the present application can be combined as needed. For example, the present invention relates to the following method for preparing a compound of formula I, which comprises the following steps:
[0037] Step 1: reacting the compound of formula II with a halogenating agent and then hydrolyzing to obtain a compound of formula III;
[0038] Step 2: reacting the compound of formula III with an oxidizing agent to obtain a compound of formula IV;
[0039] Step 3: reacting the compound of formula IV with an azidating agent to obtain a compound of formula V;
[0040] Step 4: Reducing the compound of formula V with a reducing agent to obtain a compound of formula VI;
[0041] Step 5: reacting the compound of formula VI with methyl isothiocyanate to obtain a compound of formula VII or a salt thereof;
[0042] Step 6: Oxidative desulfurization of the compound of formula VII to obtain a compound of formula I;
[0043] wherein R is H or ethyl; X is halogen selected from Cl, Br or I;
[0044] The reaction conditions of each step are as described above.
[0045] In a preferred embodiment, the above method further comprises the step of preparing pilocarpine hydrochloride or nitrate as described in the third aspect of the present application.
[0046] In a fourth aspect, the present invention provides a compound of formula V or a salt thereof:
[0047] Wherein, R is H or ethyl.
[0048] The present invention also provides a compound of formula IV or a salt thereof:
[0049] wherein R is H or ethyl, and X is halogen selected from Cl, Br or I;
[0050] With the proviso that, except for the compound of formula IV below, when R is H, X is Cl or Br; or when R is ethyl, X is Cl.
[0051] The present invention also provides the following compounds: BRIEF DESCRIPTION OF THE DRAWINGS
[0052] FIG1 shows the HPLC test results of the pilocarpine hydrochloride product obtained in Example 8. Specific implementation method:
[0053] Abbreviations and other terms used in this document:
[0054] NBS refers to N-bromosuccinimide.
[0055] PCC refers to pyridinium chlorochromate.
[0056] PDC refers to pyridinium dichromate.
[0057] DMSO refers to dimethyl sulfoxide.
[0058] DMF refers to N,N-dimethylformamide.
[0059] LDA refers to lithium diisopropylamide.
[0060] The organic solvent used is not particularly limited as long as it can dissolve the starting material compound. Preferably, the organic solvent used can be selected from one or more of toluene, hexane, n-heptane, methyl acetate, ethyl acetate, isopropyl acetate, acetonitrile, tetrahydrofuran, isopropyl ether, methyl tert-butyl ether, dichloromethane, acetone, methanol, ethanol, and isopropanol.
[0061] In the above method, there is no particular limitation on the reaction temperature, which belongs to a conventional reaction.
[0062] In the above method, conventional quenching reaction refers to adding an aqueous solution, ammonium chloride solution, hydrochloric acid solution, or phosphoric acid solution to the reaction solution to terminate the reaction or destroy the reaction system.
[0063] In the above methods, conventional extraction methods refer to the process of dissolving the reaction product in an organic solvent or dissolving the reaction product in an aqueous phase to separate it from other substances in the reaction system or to remove impurities.
[0064] The compound of formula II is prepared by referring to the method of Org.Biomol.Chem., 2017, 15, 3728-3735, CN108929289 and Organic Letters, 2011, 13, 1, 118-121 or a similar method.
[0065] The method of the present invention will be further described below by way of examples. It should be understood that the purpose of providing the following examples is merely to enable a better understanding of the present invention, and is not intended to limit the scope of the present invention in any way.
[0066] Unless otherwise stated, the raw materials and reagents used in the examples of the present invention were purchased commercially or obtained by known methods and used as received. The purity and chirality were determined by high performance liquid chromatography (HPLC). The identity of the target product was confirmed by its consistency with the HPLC retention value of the standard.
[0067] Example 1: Preparation of the compound of formula III (R is ethyl)
[0068] 39 g of compound II, 53.5 g of NBS, 450 mL of acetonitrile, and 150 mL of water were added to a four-necked flask and stirred at 25°C for 12 hours. TLC monitored the reaction completion. The reaction solution was concentrated under reduced pressure, added with 100 mL of water, and extracted with 3 × 100 mL of methyl tert-butyl ether. The organic layers were combined, washed once with water, and evaporated to dryness to yield 45.0 g of an oil (70.8% yield). The oil was carried on to the next step without purification.
[0069] Example 2: Preparation of the compound of formula IV (R is ethyl)
[0070] Add 27.0 g of compound III, 58.4 g of Dess-Martin periodinane, and 350 mL of dichloromethane to a four-necked flask and stir at 25°C for 8 hours. Monitor the reaction by TLC until completion, then quench with 200 mL of saturated NaHSO₃ solution. Separate the layers and wash the organic layer twice with NaHCO₃ solution and once with brine. Evaporate to dryness and column chromatography to yield 23.6 g of a light yellow oil (88.0% yield).
[0071] 1 H NMR(400MHz, CDCl3) δ4.53(dd,J=9.3,7.5Hz,1H),3.87(s,2H),3.79(dd,J=9.3,7.5Hz,1H),3.10–3.02(m ,1H),2.86–2.77(m,1H),2.75–2.65(m,1H),2.22–2.15(m,1H),1.74–1.68(m,2H),1.01(t,J=6.3Hz,3H).
[0072] Example 3: Preparation of the compound of formula V (R is ethyl)
[0073] 21.6 g of compound IV and 200 mL of acetone were added to a four-necked flask under nitrogen atmosphere. 8.4 g of solid NaN3 was added portionwise. Stir at 25°C for 13 hours. TLC monitored the reaction completion. 200 mL of water and 200 mL of ethyl acetate were added, and the layers were separated. The organic layer was washed three times with water. Evaporation to dryness afforded 16.7 g of an oil (91.5% yield), which was carried on to the next step without purification.
[0074] 1 H NMR (400MHz, CDCl3) δ4.47(dd,J=9.3,7.5Hz,1H),3.93(s,2H),3.72(dd,J=9.4,7.5Hz,1H),2.80(dd,J=1 7.7,4.1Hz,1H),2.68–2.50(m,2H),2.12(dt,J=8.5,6.1Hz,1H),1.70–1.50(m,2H),0.93(t,J=6.4Hz,3H).
[0075] Example 4: Preparation of the compound of formula VI (R is ethyl)
[0076] To a hydrogenation reactor, 14.7 g of compound V, 12 mL of concentrated hydrochloric acid, 150 mL of methanol, and 1.5 g of 10% palladium on carbon were added. The atmosphere was replaced with hydrogen three times, and then stirred at 25°C for 6 hours under 1 kg of hydrogen pressure. The reaction was monitored for completion by TLC. The mixture was filtered and evaporated to dryness to obtain 15.2 g of crude product (99.0% yield). The product was carried on to the next step without purification.
[0077] Example 5: Preparation of the compound of formula VII (R is ethyl)
[0078] 15.0 g of compound VI, 9.8 g of potassium carbonate, 16.3 g of methyl isothiocyanate, and 150 mL of 70% tetrahydrofuran (105 mL of tetrahydrofuran and 45 mL of water) were added to a four-necked flask and stirred at 25°C for 14 hours. The reaction was monitored for completion by TLC, concentrated under reduced pressure, and extracted with 5 × 80 mL of dichloromethane. The combined organic layers were evaporated to dryness to yield 10.7 g of a solid (65.9% yield). The solid was carried on to the next step without purification.
[0079] Example 6: Preparation of the compound of formula I (R is ethyl)
[0080] Add 10.0 g of compound VII, 180 mL of water, and 20 mL of nitric acid to a four-necked flask. Add 4.0 g of solid sodium nitrite under an ice-water bath. Incubate for 0.5 hours, then slowly raise the temperature to 25°C and react for 3 hours. Monitor the reaction by TLC. Extract impurities with 2 × 80 mL of dichloromethane and discard the organic layer. Adjust the pH of the aqueous layer to 7-8 with aqueous ammonia. Extract the product with 4 × 100 mL of dichloromethane. Combine the dichloromethane layers, evaporate to dryness, and perform column chromatography to obtain 7.49 g of liquid, with a yield of 86.4% and an ee of 27.2%.
[0081] 1 H NMR (500MHz, d-DMSO) δ9.12(s,1H),7.59(s,1H),4.41(t,J=8.2Hz,1H),3.90(t,J=8.4Hz,1H),3.80(s,3H),2.99(dd,J=15.8,5. 1Hz,1H),2.85(dd,J=15.9,9.5Hz,1H),2.74–2.63(m,1H),2.46(dt,J=8.9,6.0Hz,1H),1.66–1.57(m,2H),0.93(t,J=7.4Hz,3H).
[0082] Example 7: Preparation of the compound of formula I (R is ethyl)
[0083] Dissolve 1.8 g of compound I' in 100 mL of anhydrous tetrahydrofuran and add 6 mL of 2.0 M LDA dropwise under ice-water bath. After addition, stir at room temperature for 0.5 hour, then add 1.5 g of ethyl bromide dropwise. After addition, slowly warm to room temperature and stir for 2-3 hours. Monitor the reaction by TLC. Quench the reaction by adding saturated aqueous ammonium chloride under ice-water bath. Extract impurities twice with 30 mL of ethyl acetate. Combine the organic phases, wash with saturated brine, evaporate to dryness, and analyze by column chromatography to yield 1.5 g of a liquid with a yield of 79.4% and an ee of 25.6%.
[0084] Example 8: Preparation of hydrochloride compound (R is ethyl)
[0085] 6.0 g of compound I (ee = 27.2%) was added to a four-necked flask, 50 mL of isopropanol and 5 mL of concentrated hydrochloric acid were added, the temperature was raised to 45-50 ° C and stirred for 1-2 hours, and the mixture was concentrated under reduced pressure to obtain crude pilocarpine hydrochloride. 30 mL of isopropanol was then added, the temperature was raised to 65-75 ° C and stirred for 0.5-1.0 hours, and then slowly cooled to room temperature, filtered, and the filter cake was washed with 10 mL of isopropanol and dried to obtain 3.0 g of white pilocarpine hydrochloride.
[0086] The above 3.0 g product was added to 30 mL of isopropanol for secondary recrystallization and dried to obtain 2.6 g of pilocarpine hydrochloride with a total yield of 43.1% and ee = 99.9%, as shown in FIG1 .
[0087] 1 H NMR (500MHz, DMSO) δ9.21(d,J=0.9Hz,1H),7.62(d,J=0.9Hz,1H),4.27(dd,J=9.1,5.8Hz,1H),3.98(dt,J=14.2,7.1Hz,1H),3.82(s,3H),3.07–2 .94(m,1H),2.80(dd,J=15.4,7.0Hz,2H),2.56(dd,J=16.0,11.2Hz,1H),1.68(dp,J=14.7,7.4Hz,1H),1.58–1.47(m,1H),1.01(t,J=7.4Hz,3H).
[0088] The specific embodiments and examples described above further illustrate the objectives, technical solutions, and beneficial effects of the present invention. It should be understood that the specific embodiments and examples described above are merely illustrative of the present invention and are not intended to limit the scope of the present disclosure. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principles of the present invention shall be included within the scope of protection of the present disclosure.
Claims
1. A method for preparing a compound of formula V, comprising the following steps: Step 1: The compound of formula II reacts with a halogenating agent and then hydrolyzes to obtain a compound of formula III; Step 2: reacting the compound of formula III with an oxidizing agent to obtain a compound of formula IV; and Step 3: reacting the compound of formula IV with an azidating agent to obtain a compound of formula V; Wherein, R is H or ethyl; X is halogen selected from Cl, Br or I.
2. The method according to claim 1, wherein the halogenating agent described in step 1 is selected from one of chlorine, NCS, trichloroisocyanuric acid, dichlorohydantoin, lithium chloride, tetrabutylammonium chloride, bromine, NBS, dibromohydantoin, tribromoisocyanuric acid, lithium bromide, tetrabutylammonium bromide, iodine, diiodohydantoin, lithium iodide, sodium iodide, potassium iodide and tetrabutylammonium iodide, or a combination of two or more of these halogenating agents.
3. The method according to claim 1, wherein the oxidant in step 2 is selected from one of Dess-Martin periodinane, hydrogen peroxide, Jones reagent, PCC, PDC and Swern reagent, or a combination of two or more of these oxidants.
4. The method according to claim 1, wherein the azidation reagent in step 3 is selected from one of sodium azide, trimethylsilyl azide, diphenylphosphoryl azide, tributyltin azide, tetrabutylammonium azide, tetramethylguanidine azide and ethyl azidoacetate, or a combination of two or more of these azidation reagents.
5. A method for preparing a compound of formula I, comprising the following steps: Step 4: Reducing the compound of formula V with a reducing agent to obtain a compound of formula VI; Step 5: reacting the compound of formula VI with methyl isothiocyanate to obtain a compound of formula VII or a salt thereof; Step 6: oxidative desulfurization of the compound of formula VII to obtain a compound of formula I; Wherein, R is H or ethyl.
6. The method according to claim 5, wherein the reduction reaction described in step 4 is a catalytic hydrogenation reduction reaction or a reduction reaction using a reducing agent, wherein: The catalytic hydrogenation reduction reaction uses a combination of a catalyst and a reducing agent, wherein the catalyst is selected from Ni, Pd / C, Pt / C, PtO2, palladium barium sulfate or any combination thereof, and the reducing agent is selected from hydrogen, ammonium chloride, formic acid, ammonium formate or any combination thereof; the reducing agent used in the reduction reaction using a reducing agent is selected from one of sodium borohydride, lithium borohydride, sodium cyanoborohydride, potassium borohydride, borane, red aluminum and lithium aluminum hydride, or a combination of two or more of the reducing agents.
7. The method according to claim 5, wherein the salt in step 5 is selected from hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate or nitrate.
8. The method according to claim 5, wherein the oxidant in step 6 is selected from hydrogen peroxide, Jones reagent or sodium nitrite.
9. The method according to claim 5, when R is ethyl, it is called the compound of formula I', and the method further comprises the step of crystallizing the compound of formula I' into a salt to obtain pilocarpine hydrochloride or nitrate:
10. The method according to claim 5, when R is H, it is called the compound of formula I", the method further comprises the step of reacting the compound of formula I" with a halogenating agent CH3CH2X, and then crystallizing the salt to obtain pilocarpine hydrochloride or nitrate: in, X is a halogen selected from Cl, Br or I.
11. The method according to claim 9 or 10, wherein the salt-forming crystallization is carried out in an alcohol solvent, such as one of methanol, ethanol, n-propanol, isopropanol, n-butanol or any combination thereof, using hydrochloric acid or nitric acid.
12. The method according to any one of claims 5 to 11, comprising the following steps: Step 1: The compound of formula II reacts with a halogenating agent and then hydrolyzes to obtain a compound of formula III; Step 2: reacting the compound of formula III with an oxidant to obtain a compound of formula IV; Step 3: reacting the compound of formula IV with an azidating agent to obtain a compound of formula V; Step 4: Reducing the compound of formula V with a reducing agent to obtain a compound of formula VI; Step 5: reacting the compound of formula VI with methyl isothiocyanate to obtain a compound of formula VII or a salt thereof; Step 6: oxidative desulfurization of the compound of formula VII to obtain a compound of formula I; Wherein R is H or ethyl; X is halogen selected from Cl, Br or I; The reaction conditions of steps 1-3 are as described in any one of claims 1-4.
13. A compound of formula V or a salt thereof in, R is H or ethyl.
14. A compound of formula IV or a salt thereof in, R is H or ethyl, X is halogen selected from Cl, Br or I, Provided that: except for the compound of the following formula IV, when R is H, X is Cl or Br; or when R is ethyl, X is Cl.
15. A compound or a salt thereof, wherein the compound is selected from: