Preparation method of steroid corticoid intermediate
By using a strong acid-potassium fluoride aqueous solution to carry out a hydrolysis reaction at a specific temperature, the problem of incomplete hydrolysis in the existing technology has been solved, and the preparation of high-purity and high-yield halomethyl ketone compounds has been achieved, which is suitable for industrial production.
Patent Information
- Application Number
- CN202411466617.2
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-10-18
- Publication Date
- 2025-02-07
AI Technical Summary
Existing technologies for synthesizing steroidal halomethyl ketone compounds suffer from incomplete hydrolysis, resulting in high impurities, low chromatographic purity and yield. Furthermore, the use of hydrofluoric acid poses safety risks and limits its widespread application.
A hydrolysis reaction was carried out using a strong acid-potassium fluoride aqueous solution at a specific temperature, combined with a post-processing method, to obtain high-purity and high-yield halomethyl ketone compounds.
It enables the preparation of high-purity and high-yield halomethyl ketone compounds, with safe operation, suitable for industrial production, and suitable for use by enterprises that do not have the safety production qualifications for hydrofluoric acid.
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Abstract
Description
Technical Field
[0001] The invention belongs to the technical field of preparation of steroid hormone drug intermediates, and specifically relates to a method for preparing a class of halogenated methyl ketone compounds. Background Art
[0002] Steroidal halomethyl ketone compounds (Formula II) are important intermediates for the synthesis of various corticosteroid drugs. Usually, silaneoxy compounds of Formula I are used to construct halomethyl ketone groups through lactone exchange and hydrolysis reactions, thereby synthesizing target intermediates and corticosteroid drugs. The synthesis route is as follows:
[0003]
[0004] The synthesis method of constructing a halomethyl ketone compound of formula II from a silanoxy compound of formula I is usually divided into two processes in the prior art: first, the silanoxy compound of formula I and diisopropylamine lithium complete an intramolecular nucleophilic addition reaction under low temperature conditions in an appropriate solvent to obtain a cyclic imine lithium intermediate. Generally, this process can achieve complete conversion of the compound of formula I when there is sufficient alkali metal, the low temperature reaction temperature is appropriate, and the reaction system does not produce obvious gelation. Second, the transition state cyclic imine lithium intermediate is further hydrolyzed under the action of acid to remove the proton silicon group to obtain the target product halomethyl ketone compound of formula II. The hydrolysis strong acid reported in the existing literature mostly uses hydrochloric acid, phosphoric acid and sulfuric acid. However, for example, under the hydrolysis conditions of hydrochloric acid, phosphoric acid or sulfuric acid in the prior art, some compounds of formula I have the problem of being unable to be completely hydrolyzed, and the target halomethyl ketone compound obtained has large impurities, and the chromatographic purity, external standard content and external standard yield are all low. If sulfuric acid is used for hydrolysis, the target compound obtained is a dark red viscous gel; when hydrofluoric acid is used for hydrolysis, hydrofluoric acid is not friendly to the equipment and has major production risks. Some enterprises or parks cannot obtain the approval qualification for safe and environmentally friendly process production, so this process cannot be widely used. In view of the problems in the hydrolysis step of the above reaction, it is necessary to provide a synthesis method that is thorough in hydrolysis, safe in production, and easy to operate. Summary of the invention
[0005] The present invention aims at the problems existing in the intramolecular nucleophilic addition and hydrolysis reaction of the corticosteroid intermediate silanoxy compound of formula I to construct the halomethyl ketone compound of formula II, and provides another new hydrolysis scheme, which can be simply summarized as follows: after the intramolecular nucleophilic addition reaction of the silanoxy compound of formula I is completed, a strong acid and potassium fluoride are used for hydrolysis, and after post-treatment, a high-purity and high-yield target halomethyl ketone compound of formula II is obtained. The structures of the corticosteroid intermediate silanoxy compound of formula I and the halomethyl ketone compound of formula II of the present invention refer to:
[0006]
[0007] Among them, in the compounds of the above formulas I and II described in the present invention, R1 and R2 can be H at the same time, or form a carbon-carbon double bond; R3 and R4 can be H at the same time, or form a carbon-carbon double bond; or R3 is H and R4 is a hydroxyl group; or R3 is H and R4 is a keto group; R5 is H or CH3; R6 is H or CH3.
[0008] In particular, the structure of the reactant compound of formula I involved in the present invention is selected from the following structures:
[0009]
[0010] Specifically, the preparation method of the compound of formula II comprises the following steps: under the protection of inert gas, the compound of formula I is dissolved in a solvent, the temperature is lowered to about -70°C, an appropriate amount of lithium diisopropylamide solution is added dropwise, the temperature is controlled at -75 to -55°C for 2 to 3 hours, and the reaction is monitored by TLC until the compound of formula I is completely reacted; the feed liquid is slowly poured into a strong acid-potassium fluoride aqueous solution, and the temperature is controlled at 35 to 40°C for hydrolysis for 2 to 5 hours. After the hydrolysis is completed, the temperature is lowered, and a 50% inorganic alkali aqueous solution is added dropwise to adjust the pH to about 7 to 8. After stirring for 0.5 hours, the mixture is allowed to stand for stratification, the organic phase is separated, the aqueous phase is extracted once with a reaction solvent, and the organic phase is combined. The mixture is concentrated under reduced pressure until no liquid is dropped, a solvent is added for crystallization, filtered, the filter cake is washed, and dried in a vacuum drying oven to obtain the compound of formula II, and a sample is taken for detection, and the yield is calculated.
[0011] The above-mentioned strong acid-potassium fluoride aqueous solution is used as a strong acid reagent in the hydrolysis process. In the present invention, the strong acid-potassium fluoride aqueous solution specifically refers to sulfuric acid-potassium fluoride aqueous solution. As a preferred embodiment, sulfuric acid with a mass fraction of 60-65% of any concentration can be used. As a preferred embodiment: 63% sulfuric acid-potassium fluoride solution. The preparation method is as follows: when the compound of formula I is 1W, 1-3W potassium fluoride and 10-25V water are weighed in a plastic bottle and stirred to dissolve, then 1-3W 63% sulfuric acid is added and mixed evenly, and the temperature is reduced to 5-25°C for use. As a preferred embodiment, when the compound of formula I is 1W, 1.3-2W potassium fluoride and 15-20V water are stirred to dissolve, then 1.3-2W 63% sulfuric acid is added and mixed evenly, and the temperature is reduced to 5-25°C for use.
[0012] The hydrolysis temperature in the hydrolysis reaction of the present invention is critical. When the hydrolysis temperature is 35-40°C, it has little effect on the external standard yield of the compound of formula II; but when the hydrolysis temperature is lower than 35°C, the hydrolysis is incomplete, and when the hydrolysis temperature is higher than 40°C, it will affect the quality of the product.
[0013] In the hydrolysis step of the present invention, the system after the intramolecular nucleophilic addition reaction can be added to a sulfuric acid-potassium fluoride aqueous solution for hydrolysis, or the sulfuric acid-potassium fluoride aqueous solution can be added to the reaction system. The former method is preferred, as the hydrolysis is faster and more thorough.
[0014] The reaction solvent is preferably tetrahydrofuran or dimethyltetrahydrofuran. Based on the weight of the compound of formula I, when the compound I is 1W, the solvent is used at 6 to 20V. Preferably, the solvent can be selected at any volume of 10 to 15V.
[0015] The post-treatment of the hydrolysis step of the present invention can be carried out by crystallization using a mixed solvent of n-heptane or methanol and water. Preferably, the product obtained by crystallization using a mixed solvent of methanol and water is more loose and does not stick to the equipment. Based on the weight of the compound of formula I, if the weight of the compound of formula I is 1W, the mixed solution used for crystallization is about 2 to 4V, and V 甲醇 :V 水 Range: 9:1~5:5.
[0016] Note: In the weight-to-volume ratio referred to in the present invention, W represents weight and V represents volume. When the unit of W is g, the unit of V is mL; when the unit of W is Kg, the unit of V is L.
[0017] The specific structures (1) and (2) of the above-mentioned compound of formula I are used to demonstrate the technical effect of the present invention. With the compound of structure (1) or (2) of formula I as the reaction substrate, after intramolecular nucleophilic addition, the hydrochloric acid hydrolysis conditions reported in the prior art are adopted. The prior art has poor applicability, the substrate cannot be completely converted, the purity of the reaction solution is low, and the material quality and state are not ideal. In some specific embodiments of the present invention, the total weight yield of the corresponding compound of formula II obtained by improving the hydrolysis method of structure (1) is ≥83%, the compound purity is greater than 90%, and the external standard yield is 71%, which is higher than the existing manufacturing level in the industry; the chromatographic purity of the corresponding compound of formula II obtained by structure (2) is greater than 90%, the substrate is completely hydrolyzed, and the reaction yield is greatly improved, which provides a new path for the synthesis of such downstream drugs.
[0018] Compared with the prior art, the nucleophilic addition and hydrolysis scheme involved in preparing the halomethyl ketone compound of formula II from the steroidal corticosteroid intermediate silanoloxy compound of formula I provided by the present invention has the following advantages: 1) The hydrolysis is thorough using sulfuric acid-potassium fluoride, so that the target halomethyl ketone compound of formula II can be stably obtained in this way with high yield and good purity. 2) The scheme of the present invention has simple steps and safe operation. The obtained halomethyl ketone compound of formula II is loose and lighter in color. The materials are not easy to stick during the process, which is beneficial to the synthesis and index control of downstream corticosteroids. 3) The process of the present invention is particularly suitable for the industrial production of corticosteroid synthesis processes that do not have the approval qualification for safe production of hydrofluoric acid, and has industrial application value. BRIEF DESCRIPTION OF THE DRAWINGS
[0019] Figure 1 HPLC chromatogram of compound II of Example 1
[0020] Figure 2HPLC chromatogram of Example 4 Compound II
[0021] Figure 3 HPLC chromatogram of Example 7 Compound II DETAILED DESCRIPTION
[0022] Various exemplary embodiments of the present invention will now be described in detail. This detailed description should not be considered as limiting the present invention, but should be understood as a more detailed description of certain aspects, features, and embodiments of the present invention.
[0023] It should be understood that the terms described in the present invention are only for describing special embodiments and are not intended to limit the present invention. In addition, for the numerical range in the present invention, it should be understood that the upper and lower limits of the scope and each intermediate value therebetween are specifically disclosed. Each smaller range between the intermediate value in any stated value or stated range and any other stated value or intermediate value in the described range is also included in the present invention. The upper and lower limits of these smaller ranges can be independently included or excluded in the scope.
[0024] Unless otherwise indicated, all technical and scientific terms used herein have the same meanings as commonly understood by those skilled in the art to which the invention belongs. Although the present invention describes only preferred methods and materials, any methods and materials similar or equivalent to those described herein may also be used in the implementation or testing of the present invention. All documents mentioned in this specification are incorporated by reference to disclose and describe the methods and / or materials related to the documents. In the event of a conflict with any incorporated document, the content of this specification shall prevail.
[0025] The reagents and materials used in the examples of the present invention are all commercially available, and their quality standards meet the research and development and production requirements and needs of the industry. To further illustrate the scheme of the present invention, a structure in the general formula of the compound of formula I is used as an example in the examples to explain the specific implementation process of the present invention.
[0026] Example 1
[0027] The starting compound I is from Zhejiang Xianjun Pharmaceutical Co., Ltd., batch H2-195230807 product, with a chromatographic purity of 98.8% and an external standard content of about 98.0%.
[0028]
[0029] Add the compound of formula I (1W, 10 g) and tetrahydrofuran (12V, 120 mL) to the reaction bottle, stir at room temperature to dissolve, lower the system temperature to about -70°C, and start adding LDA solution (concentration 1.7 mol / L, about 2.4 molar equivalents of the compound of formula I) dropwise under nitrogen protection, and control the dropping temperature not higher than -60°C. After the addition is completed, keep warm for 2 to 3 hours, and monitor the reaction of the raw materials by TLC.
[0030] Prepare 63% sulfuric acid-potassium fluoride aqueous solution: weigh potassium fluoride (1.3W, 1.3 g) and water (15V, 150 mL) in a plastic bottle, stir to dissolve, then add 63% sulfuric acid (1.3W, 13 g) and mix evenly, cool to 5-25°C for use.
[0031] After the reaction is completed, the reaction system is slowly added to a 5-25°C 63% sulfuric acid-potassium fluoride aqueous solution, and the temperature is controlled at 35-40°C for hydrolysis for 2-3 hours. After the hydrolysis is completed, a 50% KOH solution is added dropwise to adjust the system pH to 7-8, and the mixture is allowed to stand for 0.5-1 hour, and the layers are separated; 2-3V tetrahydrofuran is added to the aqueous phase for washing, and the mixture is allowed to stand for 0.5-1 hour, and the layers are separated; the upper organic phase is combined, and the organic phase is concentrated under reduced pressure at 40-50°C until no liquid drops (vacuum degree <0.08Mpa), and 20mL (V methanol-water mixed solution) is added. 甲醇 :V 水 =1:1) stirred for crystallization for 1-2h, filtered, collected the filter cake, transferred the filter cake to an oven, and vacuum dried overnight to obtain 8.45g of compound II, with a weight yield of 84.5% (theoretical 87.2%), a chromatographic purity of 95.6%, and an external standard yield of 73.6%.
[0032] Example 2
[0033] The starting compound 4AD is from Zhejiang Xianjun Pharmaceutical Co., Ltd., batch G001-2023101014 product, chromatographic purity 96.8%. The reaction of this example is as follows:
[0034]
[0035] 1) Cyanidation reaction: 4AD (1.0W, 20g) and methanol (1.2V, 24mL) were added to the reaction bottle, stirring was started, acetone cyanohydrin (1.2V, 24mL) was added, and then sodium carbonate (0.1W, 2g) and water (2V, 40mL) were prepared into a solution and added to the reaction bottle, and the temperature was controlled at 40±5°C for 24h. After the reaction was completed, the temperature was lowered to about 25°C, 4V of drinking water was added for water precipitation, suction filtration was performed, the filter cake was rinsed with water until it was neutral, and vacuum dried at 30-50°C overnight to obtain 20.08g of 4AD cyanohydrin intermediate I, with a chromatographic purity of 98.01% and a weight yield of 100.4%.
[0036] 2) Etherification reaction: Under argon protection, add dichloromethane (10V, 100mL) to the reaction bottle, add 4AD cyanohydrin intermediate I (1W, 10g) and imidazole (0.4W, 4g) prepared in 1) above, cool to 0-5°C, control the temperature below 20°C and drip chloromethyldimethylsilyl chloride (0.6V, 6mL). After dripping, heat to 20-25°C and keep warm for 1-2h. TLC tracking reaction until the raw material reaction is complete. Add sodium carbonate (0.01W, 0.1g) and water (2V, 20mL) prepared solution, stir for more than 0.5h, stand for separation, concentrate the organic layer under reduced pressure to near dryness, add methanol 5V and continue to concentrate under reduced pressure to near dryness, then add methanol 1V and cool to 0-5°C, filter, rinse and dry. After vacuum drying at below 40°C overnight, about 12.48 g of compound 1 was obtained with a chromatographic purity of 99.45% and a weight yield of 124.8%.
[0037] 3) Intramolecular nucleophilic addition and hydrolysis: Compound I (1W, 10 g) prepared in step 2) above was taken, and the feed ratio and process described in Example 1 were followed to obtain 8.21 g of compound II with a chromatographic purity of 94.48% and a weight yield of 82.1%.
[0038] Example 3
[0039] The starting compound 9,11-ene-4AD is from Zhejiang Xianju Pharmaceutical Co., Ltd., batch ST-221101 product, chromatographic purity 97.5%. The reaction of this example is as follows:
[0040]
[0041] 1) Cyanidation reaction: Take the starting material 9,11-ene-4AD (1W, 20 g), and carry out the reaction according to the feed ratio and process described in step 1) of Example 2 to obtain 20.18 g of cyanohydrin intermediate I with a chromatographic purity of 98.98% and a weight yield of 100.9%.
[0042] 2) Etherification reaction: Take the cyanohydrin intermediate I (1W, 10 g) obtained in step 1) above, and carry out the reaction according to the feed ratio and process described in step 2) of reference example 2 to obtain 12.34 g of compound I with a chromatographic purity of 99.36% and a weight yield of 123.4%.
[0043] 3) Intramolecular nucleophilic addition and hydrolysis: Compound I (1W, 10 g) prepared in step 2) above was taken, and the feed ratio and process described in Example 1 were followed to obtain 8.21 g of compound II with a chromatographic purity of 91.72% and a weight yield of 78.1%.
[0044] Example 4
[0045] The starting compound 9,11-ene-16α-methyl-4AD is from Zhejiang Xianju Pharmaceutical Co., Ltd., batch C03-230530 product, chromatographic purity 97.5%. The reaction of this example is as follows:
[0046]
[0047] 1) Cyanidation reaction: Take the starting material 9,11-ene-16α-methyl-4AD (1W, 20 g), and carry out the reaction according to the feed ratio and process described in step 1) of Reference Example 2 to obtain 0.07 g of cyanohydrin intermediate I2 with a chromatographic purity of 97.41% and a weight yield of 100.35%.
[0048] 2) Etherification reaction: Take the cyanohydrin intermediate I (1W, 10 g) obtained in step 1) above, and carry out the reaction according to the feed ratio and process described in step 2) of reference example 2 to obtain 12.56 g of compound I with a chromatographic purity of 98.04% and a weight yield of 125.6%.
[0049] 3) Intramolecular nucleophilic addition and hydrolysis: Compound I (1W, 10 g) prepared in step 2) above was taken, and the feed ratio and process described in Example 1 were followed to obtain 8.12 g of compound II with a chromatographic purity of 97.34% and a weight yield of 81.2%.
[0050] Example 5
[0051] The starting compound 16α-methyl-4AD is from Zhejiang Xianjun Pharmaceutical Co., Ltd., batch ST-195230807 product, chromatographic purity 97.3%. The reaction of this example is as follows:
[0052]
[0053] The preparation process of compound 1 in this example is similar to that of example 2. According to the intramolecular nucleophilic addition and hydrolysis scheme of the present invention, compound I (1W, 10 g) was taken, and the feed ratio and process described in example 1 were referred to obtain 8.15 g of compound II with a chromatographic purity of 96.7% and a weight yield of 81.5%.
[0054] Example 6
[0055] The starting compound 19-nor-4AD was obtained from Zhejiang Xianju Pharmaceutical Co., Ltd., batch C03-230520 product, chromatographic purity 96.6%. The reaction of this example is as follows:
[0056]
[0057] The preparation process of compound 1 in this example is similar to that of example 2. According to the intramolecular nucleophilic addition and hydrolysis scheme of the present invention, compound I (1W, 10 g) was taken, and the feed ratio and process described in example 1 were referred to obtain 7.82 g of compound II with a chromatographic purity of 93.7% and a weight yield of 78.2%.
[0058] Example 7
[0059] The starting compound 11-keto-ADD was obtained from Zhejiang Xianju Pharmaceutical Co., Ltd., batch ST-240701 product, chromatographic purity 98.5%. The reaction of this example is as follows:
[0060]
[0061] The preparation process of compound 1 in this example is similar to that of example 2. According to the intramolecular nucleophilic addition and hydrolysis scheme of the present invention: compound I (1W, 10 g) was taken, and the feed ratio and process described in example 1 were referred to. The product was 7.83 g of brown-yellow powder with a chromatographic purity of 90.87% and a weight yield of 78.3%.
[0062] Comparative Example 1
[0063] The starting material I was obtained from Zhejiang Xianjun Pharmaceutical Co., Ltd., batch sample H2-195230807 product, with a chromatographic purity of 98.8% and an external standard content of about 98.0%.
[0064]
[0065] Add the compound of formula I (1W, 10 g) and tetrahydrofuran (12V, 120 mL) to the reaction bottle, stir at room temperature to dissolve, lower the system temperature to about -70°C, and start adding LDA solution (concentration 1.7 mol / L, about 2.4 molar equivalents of the compound of formula I) dropwise under nitrogen protection, and control the dropping temperature not higher than -60°C. After the addition is completed, keep warm for 2 to 3 hours, and monitor the reaction of the raw materials by TLC.
[0066] After the reaction is completed, slowly add concentrated hydrochloric acid solution (4V, 40mL) to the reaction system, control the temperature not higher than 30℃, and hydrolyze for 12h at room temperature. After the hydrolysis is completed, add 50% KOH solution to adjust the pH of the system to 7-8, let it stand for 2-3h, and separate the layers; add 2-3V tetrahydrofuran to wash the aqueous phase, let it stand for 0.5-1h, and separate the layers; combine the upper organic phases, concentrate the organic phases under reduced pressure at 40-50℃ until there is no liquid dripping (vacuum degree ≤0.08Mpa), and add 20mL (V methanol-water mixed solution) 甲醇 :V 水=1:1) stirring and crystallizing for 1-2h, suction filtration, collecting the filter cake, transferring the filter cake to an oven, and vacuum drying overnight to obtain the compound of formula II. The chromatographic purity is 80.53%. Due to the poor state of the material, the yield was not calculated, and the external standard content was not detected.
[0067] The concentrated hydrochloric acid was replaced with a 20% dilute hydrochloric acid solution, and the other operations were the same as those of the above concentrated hydrochloric acid solution to obtain the compound of formula II with a weight yield of 109.8% (theoretical yield of 87.2%), a chromatographic purity of 89.5%, and an external standard yield of 42.8%.
[0068] Comparative Example 2
[0069] Take the same starting compound I (1W, 10g) as in Example 7, and hydrolyze with concentrated hydrochloric acid according to the feed ratio and operation method of Comparative Example 1. The reaction formula of this example is as follows:
[0070]
[0071] The product was hydrolyzed at room temperature for 15 hours, and a black oily substance was obtained after post-treatment. It was found that 21% of the substrate remained unconverted, and the chromatographic purity of the compound of formula II was about 45.57%. The hydrolysis effect of hydrochloric acid was poor.
[0072] Although the present invention has been described with reference to exemplary embodiments, it should be understood that the present invention is not limited to the disclosed exemplary embodiments. Various adjustments or changes may be made to the exemplary embodiments of the present specification without departing from the scope or spirit of the present invention. The scope of the claims should be based on the broadest interpretation to cover all modifications and equivalent structures and functions.
Claims
1. A method for preparing a steroidal corticosteroid intermediate of formula II, characterized in that: The preparation method comprises: under the protection of inert gas, the compound of formula I reacts with lithium diisopropylamide in a suitable solvent at -75 to -55°C for nucleophilic addition reaction; after the compound of formula I is completely reacted, the reaction liquid is added into a hydrolysis solution prepared by potassium fluoride, sulfuric acid and water, and stirred at 35 to 40°C for 2 to 5 hours, and then a compound of formula II is obtained through a post-treatment step. The synthesis route is as follows: Wherein, the reaction solvent is tetrahydrofuran or dimethyltetrahydrofuran; the structure of the compound of formula I is selected from any one of the following structures:
2. The method for preparing the steroidal corticosteroid intermediate II according to claim 1, characterized in that: The mass fraction of sulfuric acid used in the hydrolyzate in the reaction is 60-65%.
3. The method for preparing the steroidal corticosteroid intermediate II according to claim 1, characterized in that: The post-treatment step of the preparation method is hydrolysis, and in the post-treatment step, a sulfuric acid-potassium fluoride aqueous solution is added to the reaction system.
4. The method for preparing the steroidal corticosteroid intermediate II according to claim 1, characterized in that: The post-treatment step of the preparation method comprises: adding an inorganic alkali aqueous solution to adjust the pH value to 7-8, standing for stratification, taking the upper layer, washing, filtering and concentrating, adding a mixed solution of n-heptane or methanol and water for crystallization, and obtaining the compound of formula II.
5. The method for preparing the steroidal corticosteroid intermediate II according to claim 4, characterized in that: The post-treatment step of the preparation method comprises: using a mixed solvent of n-heptane or methanol and water for crystallization; if the weight of the compound of reaction formula I is 1W, the amount of crystallization solution used for crystallization is 2-4V.
6. The method for preparing the steroidal corticosteroid intermediate II according to claim 5, characterized in that: The post-processing step of the preparation method comprises: when crystallizing using a mixed solvent of methanol and water, the volume ratio is 9:1 to 5:
5.
7. The preparation method according to claim 1, characterized in that: The weight-volume ratio of the aqueous solution prepared by the compound of formula I, reaction solvent, potassium fluoride, sulfuric acid and water is: 1W: 6-20V: 1-3W: 1-3W: 10-25V.
8. The preparation method according to claim 6, characterized in that: The weight-volume ratio of the aqueous solution prepared by the compound of formula I, the reaction solvent, potassium fluoride and sulfuric acid water is: 1W: 10-15V: 1.3-2W: 1.3-2W: 15-20V.