Regorafenib monohydrate_1019206-88-2_MSDS_MedChemExpress

广藿香醇结构式全文共四篇示例，供读者参考第一篇示例：广藿香（Magnolia officinalis），又名辣藿香、辣木香、白藿香等，是一种常见的植物，属于木兰科藿香属。

广藿香主要生长在中国、日本、朝鲜和俄罗斯等地区，是一种常见的药用植物。

广藿香的主要有效成分是广藿香醇，是一种具有多种药理作用的重要化合物。

广藿香醇的结构式为C10H18O，化学名为4-allyl-1-methoxy-2-(1-propenyl)cyclohexene，是一种萜烃类化合物。

广藿香醇是广藿香中的一种活性成分，具有多种生物活性和药理作用，被广泛应用于中药制剂、保健品和化妆品中。

广藿香醇具有镇静安神、抑制细菌、抗炎以及减轻疼痛等功效。

研究表明，广藿香醇具有抗抑郁、镇静安眠、抗氧化等作用，可有效缓解精神压力，改善睡眠质量，提高身体抵抗力。

广藿香醇还具有抗菌、抗炎和抗氧化作用，可以有效预防和治疗多种疾病。

广藿香醇的应用领域非常广泛，既可以直接作为中药成分使用，也可以应用于化妆品、保健品等领域。

广藿香醇在中药领域被广泛应用于治疗失眠、焦虑、忧郁、神经衰弱等症状，其镇静安神、抗抑郁的作用备受认可。

在化妆品领域，广藿香醇具有很好的抗氧化和抗菌功效，可以用于护肤品、美容品中，帮助净化肌肤、抗衰老和延缓皮肤衰老。

广藿香醇作为广藿香中的重要有效成分，具有多种生物活性和药理作用，被广泛应用于中药制剂、保健品和化妆品中。

其镇静安神、抗氧化、抗菌等功效备受认可，有望成为未来中药和化妆品市场中的热门产品。

随着人们对健康、自然的追求，广藿香醇的市场前景将更加广阔，对于广藿香的开发利用和推广具有积极的意义。

第二篇示例：广藿香醇，又称广香藿醇，是一种具有特殊香气的有机化合物，常被用于食品、医药和香料行业。

它的独特香气使其成为一种重要的香料和药用成分，具有镇静、抗菌、抗炎和抗氧化等多种功效。

广藿香醇的化学结构式为C10H18O，是一种萜类天然产物。

广藿香醇的结构式如下：由结构式可知，广藿香醇分子由一个环烷基和一个烯醇基组成。

雷诺嗪药典标准
雷诺嗪（Ranolazine）是一种心血管选择性抗缺血药，其药典标准主要参考美国药典（USP）或者中国药典（Ch.P）中关于雷诺嗪的规定。

以下是雷诺嗪的药典标准概述。

1.品名：雷诺嗪
2.化学名称：5-[2-[[4-[(2-氰基乙基)氨基]苯基]-1,3-二氧杂-2-丙醇]-2-甲基-1,3-二氧杂-2-丙醇
3.分子式：C24H31N3O4
4.分子量：433.51
5.CAS号：95635-55-5
6.外观：白色或类白色结晶性粉末
7.熔点：178-182℃
8.用途：抗心绞痛药
9.制剂：片剂、缓释片剂
10.规格：500mg、1000mg（美国）；375mg、500mg、750mg（英国）
需要注意的是，雷诺嗪的药典标准可能会随着不同国家和地区的药典版本而有所差异。

在实际应用中，应遵循医生开具的处方以及药品说明书上的用法用量。

如有疑问，请咨询专业医生。

INSTRUCTIONSPierce® BCA Protein Assay Kit23225 Pierce BCA Protein Assay Kit, sufficient reagents for 500 test-tube or 5000 microplate assays 23227 Pierce BCA Protein Assay Kit, sufficient reagents for 250 test-tube or 2500 microplate assays Kit Contents:BCA Reagent A, 1000mL (in Product No. 23225) or 500mL (in Product No. 23227), containingsodium carbonate, sodium bicarbonate, bicinchoninic acid and sodium tartrate in 0.1M sodiumhydroxideBCA Reagent B, 25mL, containing 4% cupric sulfateAlbumin Standard Ampules, 2mg/mL, 10 × 1mL ampules, containing bovine serum albumin (BSA)at 2mg/mL in 0.9% saline and 0.05% sodium azideStorage: Upon receipt store at room temperature. Product shipped at ambient temperature.Note: If either Reagent A or Reagent B precipitates upon shipping in cold weather or during long-termstorage, dissolve precipitates by gently warming and stirring solution. Discard any kit reagent thatshows discoloration or evidence of microbial contamination.Table of ContentsIntroduction (1)Preparation of Standards and Working Reagent (required for both assay procedures) (2)Test Tube Procedure (Sample to WR ratio = 1:20) (3)Microplate Procedure (Sample to WR ratio = 1:8) (3)Troubleshooting (4)Related Thermo Scientific Products (5)Additional Information (5)References (6)IntroductionThe Thermo Scientific Pierce BCA Protein Assay is a detergent-compatible formulation based on bicinchoninic acid (BCA) for the colorimetric detection and quantitation of total protein. This method combines the well-known reduction of Cu+2 to Cu+1 by protein in an alkaline medium (the biuret reaction) with the highly sensitive and selective colorimetric detection of the cuprous cation (Cu+1) using a unique reagent containing bicinchoninic acid.1 The purple-colored reaction product of this assay is formed by the chelation of two molecules of BCA with one cuprous ion. This water-soluble complex exhibits a strong absorbance at 562nm that is nearly linear with increasing protein concentrations over a broad working range (20-2000µg/mL). The BCA method is not a true end-point method; that is, the final color continues to develop. However, following incubation, the rate of continued color development is sufficiently slow to allow large numbers of samples to be assayed together.The macromolecular structure of protein, the number of peptide bonds and the presence of four particular amino acids (cysteine, cystine, tryptophan and tyrosine) are reported to be responsible for color formation with BCA.2 Studies with di-, tri- and tetrapeptides suggest that the extent of color formation caused by more than the mere sum of individual color-producing functional groups.2 Accordingly, protein concentrations generally are determined and reported with reference to standards of a common protein such as bovine serum albumin (BSA). A series of dilutions of known concentration are prepared from the protein and assayed alongside the unknown(s) before the concentration of each unknown is determined based on the standard curve. If precise quantitation of an unknown protein is required, it is advisable to select a proteinstandard that is similar in quality to the unknown; for example, a bovine gamma globulin (BGG) standard (see Related Thermo Scientific Products) may be used when assaying immunoglobulin samples.Two assay procedures are presented. Of these, the Test Tube Procedure requires a larger volume (0.1mL) of protein sample; however, because it uses a sample to working reagent ratio of 1:20 (v/v), the effect of interfering substances is minimized. The Microplate Procedure affords the sample handling ease of a microplate and requires a smaller volume (10-25µL) of protein sample; however, because the sample to working reagent ratio is 1:8 (v/v), it offers less flexibility in overcoming interfering substance concentrations and obtaining low levels of detection.Preparation of Standards and Working Reagent (required for both assay procedures) A.Preparation of Diluted Albumin (BSA) StandardsUse Table 1 as a guide to prepare a set of protein standards. Dilute the contents of one Albumin Standard (BSA) ampule into several clean vials, preferably using the same diluent as the sample(s). Each 1mL ampule of 2mg/mL Albumin Standard is sufficient to prepare a set of diluted standards for either working range suggested in Table 1. There will be sufficient volume for three replications of each diluted standard.Table 1. Preparation of Diluted Albumin (BSA) StandardsVial Volume of Diluent(µL)Volume and Source of BSA(µL)Final BSA Concentration(µg/mL)A 0 300 of Stock 2000B 125 375 of Stock 1500C 325 325 of Stock 1000D 175 175 of vial B dilution 750E 325 325 of vial C dilution 500F 325 325 of vial E dilution 250G 325 325 of vial F dilution 125H 400 100 of vial G dilution 25I 400 0 0 = BlankVial Volume of Diluent(µL)Volume and Source of BSA(µL)Final BSA Concentration(µg/mL)A 700 100 of Stock 250B 400 400 of vial A dilution 125C 450 300 of vial B dilution 50D 400 400 of vial C dilution 25E 400 100 of vial D dilution 5F 400 0 0 = BlankB.Preparation of the BCA Working Reagent (WR)e the following formula to determine the total volume of WR required:(# standards + # unknowns) × (# replicates) × (volume of WR per sample) = total volume WR required Example: for the standard test-tube procedure with 3 unknowns and 2 replicates of each sample:(9 standards + 3 unknowns) × (2 replicates) × (2mL) = 48mL WR requiredNote: 2.0mL of the WR is required for each sample in the test-tube procedure, while only 200 µl of WR reagent is required for each sample in the microplate procedure.2.Prepare WR by mixing 50 parts of BCA Reagent A with 1 part of BCA Reagent B (50:1, Reagent A:B). For the aboveexample, combine 50mL of Reagent A with 1mL of Reagent B.Note: When Reagent B is first added to Reagent A, turbidity is observed that quickly disappears upon mixing to yield a clear, green WR. Prepare sufficient volume of WR based on the number of samples to be assayed. The WR is stable for several days when stored in a closed container at room temperature (RT).Procedure Summary (Test-tube Procedure, Standard Protocol)Test-tube Procedure (Sample to WR ratio = 1:20)1.Pipette 0.1mL of each standard and unknown sample replicate into an appropriately labeled test tube.2.Add 2.0mL of the WR to each tube and mix well.3.Cover and incubate tubes at selected temperature and time:•Standard Protocol: 37°C for 30 minutes (working range = 20-2000µg/mL)•RT Protocol: RT for 2 hours (working range = 20-2000µg/mL)•Enhanced Protocol: 60°C for 30 minutes (working range = 5-250µg/mL)Notes:•Increasing the incubation time or temperature increases the net 562nm absorbance for each test and decreases both the minimum detection level of the reagent and the working range of the protocol.•Use a water bath to heat tubes for either Standard (37°C incubation) or Enhanced (60°C incubation) Protocol. Usinga forced-air incubator can introduce significant error in color development because of uneven heat transfer.4.Cool all tubes to RT.5.With the spectrophotometer set to 562nm, zero the instrument on a cuvette filled only with water. Subsequently, measurethe absorbance of all the samples within 10 minutes.Note: Because the BCA assay does not reach a true end point, color development will continue even after cooling to RT.However, because the rate of color development is low at RT, no significant error will be introduced if the 562nm absorbance measurements of all tubes are made within 10 minutes of each other.6.Subtract the average 562nm absorbance measurement of the Blank standard replicates from the 562nm absorbancemeasurement of all other individual standard and unknown sample replicates.7.Prepare a standard curve by plotting the average Blank-corrected 562nm measurement for each BSA standard vs. itsconcentration in µg/mL. Use the standard curve to determine the protein concentration of each unknown sample. Microplate Procedure (Sample to WR ratio = 1:8)1.Pipette 25µL of each standard or unknown sample replicate into a microplate well (working range = 20-2000µg/mL).Note: If sample size is limited, 10µL of each unknown sample and standard can be used (sample to WR ratio = 1:20).However, the working range of the assay in this case will be limited to 125-2000µg/mL.2.Add 200µL of the WR to each well and mix plate thoroughly on a plate shaker for 30 seconds.3.Cover plate and incubate at 37°C for 30 minutes.4.Cool plate to RT. Measure the absorbance at or near 562nm on a plate reader.Notes:•Wavelengths from 540-590nm have been used successfully with this method.•Because plate readers use a shorter light path length than cuvette spectrophotometers, the Microplate Procedure requires a greater sample to WR ratio to obtain the same sensitivity as the standard Test Tube Procedure. If higher 562nm measurements are desired, increase the incubation time to 2 hours.•Increasing the incubation time or ratio of sample volume to WR increases the net 562nm measurement for each well and lowers both the minimum detection level of the reagent and the working range of the assay. As long as allstandards and unknowns are treated identically, such modifications may be useful.5.Subtract the average 562nm absorbance measurement of the Blank standard replicates from the 562nm measurements ofall other individual standard and unknown sample replicates.6.Prepare a standard curve by plotting the average Blank-corrected 562nm measurement for each BSA standard vs. itsconcentration in µg/mL. Use the standard curve to determine the protein concentration of each unknown sample.Note: If using curve-fitting algorithms associated with a microplate reader, a four-parameter (quadratic) or best-fit curve will provide more accurate results than a purely linear fit. If plotting results by hand, a point-to-point curve is preferable to a linear fit to the standard points.A.Interfering substancesCertain substances are known to interfere with the BCA assay including those with reducing potential, chelating agents, and strong acids or bases. Because they are known to interfere with protein estimation at even minute concentrations, avoid the following substances as components of the sample buffer:Ascorbic Acid EGTA Iron Impure SucroseCatecholamines Impure Glycerol Lipids TryptophanCreatinine Hydrogen Peroxide Melibiose TyrosineCysteine Hydrazides Phenol Red Uric AcidOther substances interfere to a lesser extent with protein estimation using the BCA assay, and these have only minor (tolerable) effects below a certain concentration in the original sample. Maximum compatible concentrations for many substances in the Standard Test Tube Protocol are listed in Table 2 (see last page of Instructions). Substances were compatible at the indicated concentration in the Standard Test Tube Protocol if the error in protein concentration estimation caused by the presence of the substance was less than or equal to 10%. The substances were tested using WR prepared immediately before each experiment. Blank-corrected 562nm absorbance measurements (for a 1000µg/mL BSA standard + substance) were compared to the net 562nm measurements of the same standard prepared in 0.9% saline. Maximum compatible concentrations will be lower In the Microplate Procedure where the sample to WR ratio is 1:8 (v/v). Furthermore, it is possible to have a substance additive affect such that even though a single component is present at a concentration below its listed compatibility, a sample buffer containing a combination of substances could interfere with the assay.B.Strategies for eliminating or minimizing the effects of interfering substancesThe effects of interfering substances in the Pierce BCA Protein Assay may be eliminated or overcome by one of several methods. •Remove the interfering substance by dialysis or gel filtration.•Dilute the sample until the substance no longer interferes. This strategy is effective only if the starting protein concentration is sufficient to remain in the working range of the assay upon dilution.•Precipitate the proteins in the sample with acetone or trichloroacetic acid (TCA). The liquid containing the substance that interfered is discarded and the protein pellet is easily solubilized in ultrapure water or directly in the alkaline BCA WR.4A protocol detailing this procedure is available from our website. Alternatively, Product No. 23215 may be used (seeRelated Pierce Products).•Increase the amount of copper in the WR (prepare WR as 50:2 or 50:3, Reagent A:B), which may eliminate interference by copper-chelating agents.Note: For greatest accuracy, the protein standards must be treated identically to the sample(s).Related Thermo Scientific Products15041 Pierce 96-Well Plates, 100/pkg.15075 Reagent Reservoirs, 200/pkg.15036 Sealing Tape for 96-Well Plates, 100/pkg.23209 Albumin Standard Ampules, 2mg/mL, 10 × 1mL ampules, containing bovine serum albumin (BSA) 23208 Pre-Diluted Protein Assay Standards: Bovine Serum Albumin (BSA) Set, 7 × 3.5mL23212 Bovine Gamma Globulin Standard, 2mg/mL, 10 × 1mL ampules23213 Pre-Diluted Protein Assay Standards, (BGG) Set, 7 × 3.5mL aliquots23235 Pierce Micro BCA Protein Assay Kit, working range of 0.5-20µg/mL23236 Coomassie Plus (Bradford) Assay Kit, working range of 1-1500µg/mL23215 Compat-Able™ Protein Assay Preparation Reagent Set23250Pierce BCA Protein Assay Kit−Reducing Agent CompatibleAdditional InformationA.Please visit our website for additional information including the following items:•Frequently Asked Questions•Tech Tip protocol: Eliminate interfering substances from samples for BCA Protein AssayB.Alternative Total Protein Assay ReagentsIf interference by a reducing substance or metal-chelating substance contained in the sample cannot be overcome, try the Thermo Scientific Coomassie Plus (Bradford) Assay Kit (Product No. 23236), which is less sensitive to such substances.C.Cleaning and Re-using GlasswareExercise care when re-using glassware. All glassware must be cleaned and given a thorough final rinse with ultrapure water.D.Response characteristics for different proteinsEach of the commonly used total protein assay methods exhibits some degree of varying response toward different proteins. These differences relate to amino acid sequence, pI, structure and the presence of certain side chains or prosthetic groups that can dramatically alter the protein’s color response. Most protein assay methods use BSA or immunoglobulin (IgG) as the standard against which the concentration of protein in the sample is determined (Figure 1). However, if great accuracy is required, prepare the standard curve from a pure sample of the target protein.Typical protein-to-protein variation in color response is listed in Table 3. All proteins were tested at 1000µg/mL using the 30-minute/37°C Test Tube Protocol. The average net color response for BSA was normalized to 1.00 and the average net color response of the other proteins is expressed as a ratio to the response of BSA.Figure 1: Typical color response curves for BSA and BGG using the Standard Test Tube Protocol (37°C/30-minute incubation). Table 3. Protein-to-protein variation. Absorbance ratios (562nm) for proteins relative to BSA using Protein Tested Ratio Albumin, bovine serum 1.00 Aldolase, rabbit muscle 0.85 α-Chymotrypsinogen, bovine 1.14 Cytochrome C, horse heart 0.83 Gamma globulin, bovine1.11 IgG, bovine 1.21 IgG, human 1.09 IgG, mouse 1.18 IgG, rabbit 1.12 IgG, sheep1.17 Insulin, bovine pancreas 1.08 Myoglobin, horse heart0.74 Ovalbumin 0.93 Transferrin, human 0.891.02 Standard Deviation 0.15Coefficient of Variation14.7%Cited References1. Smith, P.K., et al. (1985). Measurement of protein using bicinchoninic acid. Anal. Biochem . 150:76-85.2. Wiechelman, K., et al. (1988). Investigation of the bicinchoninic acid protein assay: Identification of the groups responsible for color formation. Anal Biochem . 175:231-7.3. Kessler, R. and Fanestil, D. (1986). Interference by lipids in the determination of protein using bicinchoninic acid. Anal. Biochem . 159:138-42.4.Brown, R., et al. (1989). Protein measurement using bicinchoninic acid: elimination of interfering substances. Anal. Biochem . 180:136-9.Product ReferencesAdilakshami, T. and Laine, R.O. (2002). Ribosomal protein S25 mRNA partners with MTF-1 and La to provide a p53-mediated mechanism for survival ordeath. J. Biol. Chem. 277:4147-51.Fischer, T., et al. (1999). Clathrin-coated vesicles bearing GAIP possess GTPase-activating protein activity in vitro. Proc. Nat. Acad. Sci. 96:6722-7. Prozialeck, W.C., et al. (2002). Chlamydia trachomatis disrupts N-cadherin-dependent cell-cell junctions and sequester β-catenin in human cervicalepithelial cells. Infection and Immunity 70:2605-13.Roberts, K.P., et al. (2002). A comparative analysis of expression and processing of the rat epididymal fluid and sperm-bound forms of proteins D and E.Biology of Reproduction 67:525-33.Triton ® is a registered trademark of Rohm & Haas Co.Brij ®, Tween ® and Span ® are registered trademarks of ICI Americas. Zwittergent ® is a registered trademark of American Hoechst Corporation.This product (“Product”) is warranted to operate or perform substantially in conformance with published Product specifications in effect at the time of sale, as set forth in the Product documentation, specifications and/or accompanying package inserts (“Documentation”) and to be free from defects in material and workmanship. Unless otherwise expressly authorized in writing, Products are supplied for research use only. No claim of suitability for use in applications regulated by FDA is made. The warranty provided herein is valid only when used by properly trained individuals. Unless otherwise stated in the Documentation, this warranty is limited to one year from date of shipment when the Product is subjected to normal, proper and intended usage. This warranty does not extend to anyone other than the original purchaser of the Product (“Buyer”).No other warranties, express or implied, are granted, including without limitation, implied warranties of merchantability, fitness for any particular purpose, or non infringement. Buyer’s exclusive remedy for non-conforming Products during the warranty period is limited to replacement of or refund for the non-conforming Product(s).There is no obligation to replace Products as the result of (i) accident, disaster or event of force majeure, (ii) misuse, fault or negligence of or by Buyer, (iii) use of the Products in a manner for which they were not designed, or (iv) improper storage and handling of the Products.Current product instructions are available at /pierce . For a faxed copy, call 800-874-3723 or contact your local distributor. © 2011 Thermo Fisher Scientific Inc. All rights reserved. Unless otherwise indicated, all trademarks are property of Thermo Fisher Scientific Inc. and its subsidiaries. Printed in the USA.Table 2. Compatible substance concentrations in the BCA Protein Assay (see text for details).§* Diluted with ultrapure water.** Detergents were tested using high-purity Thremo Scientific Surfact-Amps Products, which have low peroxide content.-- Dashed-line entry indicates that the material is incompatible with the assay.§ For a more extensive list of substances, download Tech Tip # 68: Protein Assay Compatibility Table from our website. This Tech Tip includes compatible substances for all of our protein assays and enables easy comparisons.。

Query1. QueryView in Reaxys87.7 %13:Tiotropium bromide31.5 g (0.1 mol) methylscopinium hexafluorophosphate (Example 9) and 30.5 g (0.10 mol) of 2,2'-methyl dithienylgly-colate are dissolved in 400 ml acetone and stirred in the presence of 90 g of zeolite of type 4A (Na12Al12Si12O48.x.nH2O) and 0.2 g (1 mmol) potassium-tert.-butoxide over a period of 20-24 hours at 0° C.The reaction mixture is filtered,the filtrate is combined with a solution of 8.7 g of LiBr (8.7 g 0.10 mol in 100 ml acetone).The product that crystallisesout is separated off by filtration, washed with acetone and then dried.A yield of 41.4 g (87.7percent) is obtained, witha 90percent conversion level.Stage 1:With potassium tert-butylate in acetone, Time= 20 - 24h, T= 0 °C , Molecular sieveStage 2:With lithium bromide in acetone, Product distribution / selectivityPatent; Brandenburg, Joerg; US2010/63289; (2010); (A1) EnglishView in Reaxys87.7 %6:EXAMPLE 6Tiotropium bromide31.5 g (0.1 mol) methylscopinium hexafluorophosphate (Example 1) and 30.5 g (0.10 mol) of 2,2'-methyl dithienylgly-colate are dissolved in 400 ml acetone and stirred in the presence of 90 g of zeolite of type 4 Å (Na12Al12Si12O48*nH2O) and 0.2 g (1 mmol) potassium-tert.-butoxide over a period of 20-24 hours at 0° C.The reaction mixture is filtered, the filtrate is combined with a solution of 8.7 g of LiBr (8.7 g 0.10 mol in 100 ml acetone).The product that crystallises out is separated off by filtration, washed with acetone and then dried.A yield of 41.4 g (87.7percent) is obtained, with a 90percent conversion level.Stage 1:With potassium tert-butylate, zeolite Na12Al12Si12O48*nH2O 4 Å in acetone, T= 0 °CStage 2:With lithium bromide in acetone, Product distribution / selectivityPatent; BOEHRINGER INGELHEIM PHARMA GMBH and CO. KG; US2010/105898; (2010); (A1) EnglishView in Reaxys48 %5:Example 5 Tiotropium Bromide 1.6 g (5 mmol) methylscopinium hexafluorophosphate (Example 1) and 1.25 g (5mmol) methyl dithienylglycolate are stirred in 50 ml acetone and in the presence of 2 g powdered molecular sieve 4A(Fluka) and 6 mg potassium-tert.-butoxide at 0° C. for 4 h. The reaction mixture is filtered, washed with 20 ml acetone,the filtrate is combined stepwise with a solution of 0.7 g LiBr (13 mmol) in 11 ml acetone. The unreacted material thatcrystallises out is separated off by filtration (fractionated precipitation). The crystal fractions were filtered off and dried.The composition of the fractions was determined by thin layer chromatography. The tiotropium bromide fractions weresuction filtered, washed with acetone, recrystallised from water, washed with acetone and dried. 1.2 g (48percent yieldbased on the compound according to Example 1 used). Tiotropium bromide was isolated in this way. Purity HPLC:99.8percent, TLC: no visible contaminationStage 1:With potassium tert-butylate in acetone, Time= 4h, T= 0 °C , Molecular sieveStage 2:With lithium bromide in acetone, Product distribution / selectivityPatent; Boehringer Ingelheim Pharma GmbH and Co. KG; US2007/27320; (2007); (A1) EnglishView in Reaxys35 %4:Example 2 Tiotropium Bromide 1.6 g (5 mmol) methylscopinium hexafluorophosphate (Example 1) and 2.0 g (7.8mmol) methyl dithienylglycolate are refluxed in 50 ml acetone and in the presence of 10 g molecular sieve 4A for 50-70hours. The reaction mixture is filtered, the filtrate is combined with a solution of 0.3 g of LiBr in 10 ml acetone. The stillunreacted N-methylscopinium bromide that crystallises out is separated off by filtration. After the addition of another0.6 g LiBr (dissolved in acetone) tiotropium bromide is precipitated in an isolated yield of 30percent (based on thecompound of Example 1 used).Stage 1:With 4-(N,N-dimethlyamino)pyridine in acetone, Time= 24h, Molecular sieve, Heating / refluxStage 2:With lithium bromide in acetone, Product distribution / selectivityPatent; Boehringer Ingelheim Pharma GmbH and Co. KG; US2007/27320; (2007); (A1) EnglishView in Reaxys30 %2:Example 2 Tiotropium Bromide 1.6 g (5 mmol) methylscopinium hexafluorophosphate (Example 1) and 2.0 g (7.8mmol) methyl dithienylglycolate are refluxed in 50 ml acetone and in the presence of 10 g molecular sieve 4A for 50-70hours. The reaction mixture is filtered, the filtrate is combined with a solution of 0.3 g of LiBr in 10 ml acetone. The stillunreacted N-methylscopinium bromide that crystallises out is separated off by filtration. After the addition of another0.6 g LiBr (dissolved in acetone) tiotropium bromide is precipitated in an isolated yield of 30percent (based on the compound of Example 1 used).Stage 1:in acetone, Time= 50 - 70h, Heating / reflux, Molecular sieveStage 2:With lithium bromide in acetone, Product distribution / selectivityPatent; Boehringer Ingelheim Pharma GmbH and Co. KG; US2007/27320; (2007); (A1) EnglishView in Reaxystropium bromide obtained was found to have the XRPD,DSC and TGA spectra shown in Figures 1, 2 and 3 respec-tively.Molar yield = 97.76percentHPLC purity = 99.83percentin dichloromethane, acetonitrile, Time= 30.3333h, T= 25 - 30 °CPatent; GENERICS [UK] LIMITED; MYLAN INDIA PRIVATE LIMITED; GORE, Vinayak Govind; MANOJKUMAR,Bindu; SHINDE, Dattatraya; KOKANE, Dattatrey; WO2011/15883; (2011); (A1) EnglishView in Reaxys97.76 %Tiotropium Bromide (1)The purified tiotropium base (3) (1 eq) was dissolved in DCM (10 vol) and acetonitrile (3 vol)and purged with methyl bromide gas for 20 minutes. The solution was kept at 25-300C for 30 hours. The precipitatedsolid was filtered and washed with DCM (20 vol). Drying of the solid at 25-300C under vacuum gave the product,tiotropium bromide (1), as a white solid.Molar yield = 97.76percentHPLC purity = 99.83percent1H NMR (300 MHz,CD3OD): 7.45 (2H dd), 7.23 (2H dd), 7.00 (2H dd), 5.27 (IH t), 4.60 (IH br s OH), 3.35 (8H m), 3.10 (2H s), 2.85 (2Hdt), 2.10 (2H d).MS: 392.3 (M+l)in dichloromethane, acetonitrile, Time= 30.3333h, T= 20 - 30 °CPatent; GENERICS [UK] LIMITED; MYLAN INDIA PRIVATE LIMITED; GORE, Vinayak Govind; MANOJKUMAR,Bindu; SHINDE, Dattatraya; KOKANE, Dattatrey; WO2011/15884; (2011); (A1) EnglishView in Reaxys97.2 %11:Example 11: Synthesis of tiotropium bromideExample 11: Synthesis of tiotropium bromide A solution of 22percent methyl bromide in acetone was prepared byscrubbing gas into a dark glass bottle containing 1.6 kg of acetone and placed on scales until obtaining 1.95 kg ofmethyl bromide solution in acetone.In a reaction flask were charged, in this order:scopine ester (3): 242.6g (0.6426moles, 1 eq) DMF: 388 mL,acetone: 1370 mL(acetone/DMF ratio: about 3.5:1)The suspension, maintained under me-chanical stirring, was heated to 40±5°C until obtaining complete dissolution of the solid.The clear (pale yellow colored)solution was cooled to 20°C and, keeping the flask immersed in a water bath, a 22.1percent (w/w) solution of methylbromide in acetone: 636 mL, equal to about 1.8 eq. of MeBr, was rapidly dropped, by addition funnel, on the clearsolution.In a few hours of stirring at room temperature, a progressive precipitation of white solid was observed.Thereaction mixture was maintained under stirring at room temperature. after about 4 days (90-100 h) a sampling wascarried out for reaction control.The reaction mixture appeared as a heterogeneous suspension made up of clear motherwaters and grainy and heavy solid, which tended to rapidly settle on the flask bottom.The solid was filtered, and flaskand solid were washed over a filter with: 863 mL of acetone/DMF mixture (5:1), 431 mL of acetone/DMF mixture (5:1),2x431 mL of acetone. The solid thus obtained was dried over the filter under Nitrogen current for 2-3h. At the end ofthe drying the solid appeared white and powdery.Crude dry Tiotropium bromide weight: 295.1 g (yield=97.2percent) .in N,N-dimethyl-formamide, acetone, T= 20 °CPatent; LUSOCHIMICA S.P.A.; CIPOLLONE, Amalia; FATTORI, Daniela; FINCHAM, Christofer Ingo;WO2013/46138; (2013); (A1) EnglishView in Reaxys97.3%2:preparation of crude tiotropium bromideN-demethyltiotropium (66 g; 0.17 mol) was dissolved in dimethylformamide (330 ml) and the solution was cooled to atemperature between 0 °C and 5 °C. A solution of bromomethane in 2-methyltetrahydrofuran (132 ml; 0.72 mol) wasadded and the reaction mixture stirred overnight at 0 °C - 5 °C. The content of N-demethyltiotropium in the reactionmixture was 3.6percent by HPLC. Then the reaction mixture was heated up to a temperature between 10 °C and 15°C and stirred at this temperature range over 2 hours. The content of N-demethyltiotropium in the reaction mixturedecreased to 1.7percent. The reaction mixture was heated to a temperature between 25 °C and 30 °C and stirred atthat temperature range over 1 hour. The content of N- demethyltiotropium in the reaction mixture decreased to 1.0per-cent by HPLC. 2- Methyltetrahydrofuran (594 ml) was added to the reaction mixture previously cooled to 0 °C - 5 °C,the suspension was stirred over 1 hour while maintaining the temperature between 0 °C and 5 °C, the product wasfiltered and washed with 2-methyltetrahydrofuran (297 ml) previously cooled to a temperature between.0 °C and 5 °C.The purity of the wet product was 99.48percent and the content of N-demethyltiotropium was 0.33percent (by HPLC).The wet product was re-s urried in dimethylformamide (297 ml) over 1 hour, was filtered, was washed with 2- methyl-tetrahydrofuran (297 ml) previously cooled' to 0 °C - 5 °C and dried. Crude tiotropium bromide (804 g; 97.3percent ofthe theoretical yield) was obtained with a purity of .99.77percent and with a residual content of N-demethyltiotropiumof 0.16percent (by HPLC) . -in 2-methyl tetrahydrofuran, N,N-dimethyl-formamide, T= 0 - 30 °CPatent; HOVIONE INTERNATIONAL LTD; KING, Lawrence; SOBRAL, Luis; TEMTEM Marcio; ANTUNES, Rafael;NUNES, Bruna; WO2013/117886; (2013); (A1) EnglishView in Reaxys95 %Preparation of Anhydrous Tiotropium Bromide from Scopine di-(2-thienyl)glycolatePreparation of Anhydrous Tiotropium Bromide from Scopine di-(2-thienyl)glycolateScopine di-(2-thienyl)glycolate (1 eq) was dissolved in acetone (35 vol) at 25-30° C. and methyl bromide in acetonitrile(50percent w/w solution, 5 vol) was added.The mixture was stirred at 25-30° C. for 24 hours and the precipitated solid was filtered and washed with acetone (5vol).The solid was dried at 60° C. under vacuum to afford the product as a white solid.The crude anhydrous tiotropium bromide obtained was found to have the XRPD, DSC and TGA spectra shown in , 2and 3 respectively.Molar yield=95percentHPLC purity=99.5-99.7percentPurification of Anhydrous Tiotropium Bromidein acetone, acetonitrile, Time= 24h, T= 25 - 30 °CPatent; GENERICE (UK) LIMITED; US2012/149725; (2012); (A1) EnglishView in Reaxys88 % 2.c:c) Preparation of the Tiotropium BromideMethyl bromide (5.1 kg) is piped into the scopine ester solution obtained by the method described above at 20° C. Thecontents of the apparatus are stirred at 30° C. for about 2.5 days. 70 L of DMF are distilled off at 50° C. in vacuo. Thesolution is transferred into a smaller apparatus. It is rinsed with DMF (10 L). Additional DMF is distilled off at 50° C. invacuo until a total amount of distillate of about 100 L is obtained. This is cooled to 15° C. and stirred for 2 hours at thistemperature. The product is isolated using a suction filter drier, washed with 15° C. cold DMF (10 L) and 15° C. coldacetone (25 L). It is dried at max. 50° C. for max. 36 hours in a nitrogen current. Yield: 13.2 kg (88percent); [0060]Melting point: 200-230° C. (depending on the purity of the starting product); [0061] The crude product thus obtained(10.3 kg) is added to methanol (66 L). The mixture is refluxed to dissolve it. The solution is cooled to 7° C. and stirredfor 1.5 h at this temperature. The product is isolated using a suction filter drier, washed with 7° C. cold methanol (11L) and dried for max. 36 h at about 50° C. in a nitrogen current. [0062] Yield: 9.9 kg (96percent); [0063] Melting point:228° C. (determined by TLC at a heating rate of 10 K/min). [0064] If desired, the product thus obtained may be convertedin the crystalline monohydrate of tiotropium bromide. The following method may be used. [0065] 15.0 kg of tiotropiumbromide are added to 25.7 kg of water in a suitable reaction vessel. The mixture is heated to 80-90° C. and stirred atconstant temperature until a clear solution is formed. Activated charcoal (0.8 kg), moistened with water, is suspendedin 4.4 kg of water, this mixture is added to the solution containing tiotropium bromide and rinsed with 4.3 kg of water.The mixture thus obtained is stirred for at least 15 min. at 80-90° C. and then filtered through a heated filter into anapparatus which has been preheated to an outer temperature of 70° C. The filter is rinsed with 8.6 kg of water. Thecontents of the apparatus are cooled to a temperature of 20-25° C. at a rate of 3-5° C. every 20 minutes. Using coldwater the apparatus is cooled further to 10-15° C. and crystallisation is completed by stirring for at least another hour.The crystals are isolated using a suction filter drier, the crystal slurry isolated is washed with 9 L of cold water (10- 15°C.) and cold acetone (10-15° C.). The crystals obtained are dried at 25° C. for 2 hours in a nitrogen current. [0066]Yield: 13.4 kg of tiotropium bromide monohydrate (86percent of theory). [0067] Melting point: 230° C. (determined byTLC at a heating rate of 10 K/min).in DMF (N,N-dimethyl-formamide), Time= 60h, T= 20 - 30 °CPatent; Boehringer Ingelheim Pharma GmbH and Co. KG; US2003/236409; (2003); (A1) EnglishView in Reaxys2; 3:Example 2: Preparation of crude Tiotropium bromide <n="29"/>[0109] 0.52 g of N-demethyl tiotropium (1.39 mmol)was suspended in 5.23 iriL of CH3CN under nitrogen.[0110] 1.35 g of CH3Br 50percent w/w solution in CH3CN (0.0071mol) were loaded, and the suspension was left under stirring at 220C for 12 hours. The product was filtered and washedwith ImI of CH3CN.[0111] 572 mg of wet Tiotropium bromide were obtained (HPLC purity 99.89percent, dithienylglycolicacid not detected).; Example 3 : Preparation of Tiotropium bromide[0112] 4.96g of N-demethyl tiotropium (13.2 mmol)were loaded in a flask under nitrogen with 49.6mL of CH3-CN. A suspension was obtained. 12.61g of CH3Br 50percentw/w -CH3CN solution- (0.066 mol) were loaded.[0113] The suspension was left under stirring at 22°C for 64 hours. Theproduct was filtered and washed with 2mL of CH3CN. [0114] 6.93g of wet Tiotropium were obtained, and dried undervacuum at 45°C for 22h (residual pressure 4 mbar) . 5.9 g of dry product (purity 99.8percent, dithienylglycolic acid-notdetected) were obtained.in acetonitrile, Time= 12 - 64h, T= 22 °C , Product distribution / selectivityPatent; SICOR INC.; WO2007/75838; (2007); (A2) EnglishView in ReaxysPreparation of anhydrous tiotropium bromide from scopine di-(2-thienyl)glycolateScopine di-(2-thienyl)glycolate (1 eq)was dissolved in acetone (35 vol) at 25-30°C and methyl bromide in acetonitrile (50percent w/w solution, 5 vol) wasadded. The mixture was stirred at 25-3O0C for 24 hours and the precipitated solid was filtered and washed with acetone(5 vol). The solid was dried at 60°C under vacuum to afford the product as a white solid. The crude anhydrous tiotropiumbromide obtained was found to have the XRPD, DSC and TGA spectra shown in Figures 1, 2 and 3 respectively.Molaryield = 95percentHPLC purity = 99.5-99.7percentPurification of anhydrous tiotropium bromideCrude anhydrous tio-teopium bromide (1 eq) was taken in DMSO (2 vol) and stirred for 1 hour at 25-3O0C. Acetone (25 vol) was slowlyadded and the mixture was chilled to 0-5°C and stirred at 0-5°C for 30 minutes. The solid was filtered and washed withacetone (3 vol) and dried under vacuum at 600C for 12 hours. The purified anhydrous tiotropium bromide obtained wasfound to have the XRPD, DSC and TGA spectra shown in Figures 1, 2 and 3 respectively.Molar yield = 98percentHPLCpurity > 99.9percentThe crude and purified samples of anhydrous tiotropium bromide prepared in the above exampleswere found to be substantially pure polymorphically with no levels of other- forms detected (>99.7percent polymorph-ically pure, as measured by XRPD). The purified anhydrous tiotropium bromide prepared was also found to be verystable chemically and polymorphically with no conversion over time to other polymorphs. The stability of the samplewas tested by subjecting the sample to accelerated stability conditions (400C + 2°C temperature and 75percent +/-5percent relative humidity) for 6 months. The chemical purity (measured by related substances and purity assays byHPLC) and polymorphic purity (measured by XRPD, DSC and TGA) were monitored for 6 months and the sample wasfound to be chemically and polymorphically stable even after 6 months under accelerated stability conditions.TheXRPDs were recorded on a Bruker D8 Advance Diffractometer, using Cu Kαl radiation as the X-ray source and LynxEyeas the detector, with a 2ψ range of from 3° to 50°, a step-size of 0.05° and a time/step of lsec.The DSCs were recordedon a Perkin Elmer Pyris 6 Instrument over a temperature range of from 250C to 25O0C at a rate of heating of 10°C/min.The TGAs were recorded on a Perkin Elmer Pyris 1 Instrument over a temperature range of from 250C to 250°C at arate of heating of 10°C/min.in acetone, acetonitrile, Time= 24h, T= 25 - 30 °CPatent; GENERICS [UK] LIMITED; MYLAN INDIA PRIVATE LIMITED; GORE, Vinayak Govind; MANOJKUMAR,Bindu; SHINDE, Dattatraya; KOKANE, Dattatrey; WO2011/15882; (2011); (A2) EnglishView in Reaxys2.65 g2:Example 22.0 g of scopine di(2-thienyl)glycolate (5.3 mmol) was dissolved in 20 ml of a mixture of dichloromethane (8 ml) andacetonitrile (12 ml) at 55°C. The solution was cooled down to 33°C and 5.46 g of 55percent MeBr in acetonitrile (5.1equivalents) was added. The solution was stirred and left to cool freely without stirring still for 48 hours. The formedcrystalline product was filtered, washed with 30 ml of dichloromethane, and dried in a vacuum oven at 35°C for 6 hours.2.65 g of white crystals were obtained,HPLC purity 99.60percent. The content of solvents (determined by GC): di-chloromethane 69,000 ppm, acetonitrile 8,200 ppm.in dichloromethane, acetonitrile, Time= 48h, T= 20 °C , Concentration, TimePatent; ZENTIVA K.S.; CERNA, Igor; RIDVAN, Ludek; KRAL, Vladimir; HAJICEK, Josef; DAMMER, Ondrej;WO2013/79040; (2013); (A1) EnglishView in Reaxys30.8 g3:Example 3 (Reference example according to the method of patent EP0418716)23.6 g of the scopine ester I (39.7 mmol) was dissolved in 230 ml of a mixture of dry dichloromethane (90 ml) and dryacetonitrile (140 ml) at 55°C, then the solution was cooled to 33°C and 54.0 g of 55percent MeBr in dry acetonitrile (5.0equivalents) were added. The solution was left to cool freely and then it was stirred at the room temperature for 19hours. The resulting crystalline product was filtered, washed with 900 ml of dichloromethane and dried in a vacuumdrier (5 kPa) at 35°C for 17 hours. 30.8 g of white crystals were obtained, HPLC purity 99.74percent. The content ofsolvents (measured with gas chromatography): dichloromethane 67000 ppm, acetonitrile 4300 ppm.in dichloromethane, acetonitrile, Time= 19h, T= 20 - 33 °CPatent; ZENTIVA, K.S.; CERNA, Igor; HAJICEK Josef; WO2013/135219; (2013); (A1) EnglishView in Reaxys30.8 g7; 9:Quaternization of the scopine ester I with methyl bromideExample 9 (Reference example reproducing the method of patent EP0418716) 23.6 g of the scopine ester I (39.7 mmol)was dissolved in 230 ml of a mixture of dry dichloromethane (90 ml) and dry acetonitrile (140 ml) at 55°C, then thesolution was cooled to 33°C and 54.0 g of 55percent MeBr in dry acetonitrile (5.0 equivalents) were added. The solutionwas left to cool down freely, and subsequently stirred at the room temperature for 19 hours. The resulting crystallineproduct was filtered, washed with 900 ml of dichloromethane and dried in a vacuum drier (5 kPa) at 35 °C for 17 hours.30.8 g of white crystals were obtained, UPLC purity 99.74percent. Solvent content (determined by gas chromatogra-phy): dichloromethane 67000 ppm, acetonitrile 4300 ppm.in dichloromethane, acetonitrile, Time= 19h, T= 20 - 33 °CPatent; ZENTIVA, K.S.; CERNA, Igor; HAJICEK, Josef; WO2013/143510; (2013); (A1) EnglishView in Reaxys15.51 g3:Preparation of Tiotropium Bromide (1) in NMPExample 3Preparation of Tiotropium Bromide (1) in NMPTo a solution of 13.2 g (39.1 mmol) desmethyl-tiotropium (4) in 30 mL NMP, 16.5 mL (115 mmol, 2.93 eq.) of a 1:1 (w/w) solution of methyl bromide in NMP were added.The mixture was stirred overnight at room temperature, whereupon a dense suspension formed.After addition of 20 mL acetonitrile, the suspension was filtered, washed with 20 mL acetonitrile, and dried with highvacuum overnight at 30° C., yielding 15.51 g of off-white powder.Residual solvents were detected by GC analysis.The XRPD pattern complied with the one shown in .1H-NMR (300 MHz, d-DMSO): 7.52 (dd, J=5.0 Hz, 1.1, 2H), 7.41 (s, 1H), 7.13 (dd, J=3.6, 1.1 Hz, 2H), 7.01 (dd, J=5.0,63.7 Hz, 2H), 5.12 (t, J=5.8 Hz, 1H),4.13 (bd, J=5.8 Hz, 2H), 3.50 (s, 2H), 3.25 (s, 3H), 3.05 (s, 3H), 2.8-2.6 (m, 2H),1.93 (s, 1H), 1.87 (s, 1H).13C-NMR (75.5 MHz, d-DMSO): 170.2, 147.1, 127.3, 126.7, 126.3, 76.8, 65.0, 64.2, 56.5, 54.1, 47.6, 28.7.6in 1-methyl-pyrrolidin-2-one, T= 20 °CPatent; CERBIOS-PHARMA SA; MEREU, Andrea; MOROSOLI, Moreno; PENNE', Umberto; PERSEGHINI,Mauro; US2014/303373; (2014); (A1) EnglishView in Reaxys(37.5 mmol) scopine methobromide are added and a solution of 2.59 g (38 mmol) imidazole and 1.52 g (38 mmol)sodium hydride (60percent) in 30 ml dimethylacetamide is added dropwise at 20° C. and the mixture is stirred for 1 hat 20° C. After cooling to -4° C. 50 ml of a 33percent solution of hydrogen bromide in glacial acetic acid are addeddropwise while the temperature does not exceed 20° C. Then 50 ml methanol are added and the mixture is stirred for3 h at 20° C. The reaction mixture is extracted with 500 ml toluene and, after separation of the toluene phase, crystallisedfrom 150 ml isopropanol at 0° C. The crude product is filtered off, washed with 30 ml cold isopropanol and dried invacuo. Yield 14.1 g (80percent, based on scopine methobromide).Stage 1:With chloro-trimethyl-silane, 1,1'-carbonyldiimidazole in isobutyramide, Time= 0.5h, T= 20 °CStage 2:With 1H-imidazole, sodium hydride in isobutyramide, Time= 1h, T= 20 °CStage 3:With methanol, hydrogen bromide in isobutyramide, acetic acid, Time= 3h, T= -4 - 20 °C , Product distribution /selectivityPatent; Boehringer Ingelheim Pharma GmbH and Co., KG; US2006/47120; (2006); (A1) EnglishView in Reaxys48 %9:17.9 g (165 mmol) chlorotrimethylsilane are added dropwise at 0° C. to a solution of 39.3 g (150 mmol) sodiumdithienylglycolate in 117 ml tetrahydrofuran. After 60 min stirring at 10-20° C. the mixture is cooled to 0° C. and a solutionof 24.3 g (150 mmol) carbonyldiimidazole in 105 ml dimethylformamide is added dropwise. After a further 30 min stirring30.3 g (121 mmol) scopine methobromide are added and the mixture is stirred for a further 60 min at 10-20° C. It iscooled to 10° C. and a solution of 16.8 g (150 mmol) potassium tert. butoxide in 90 ml tetrahydrofuran is added dropwiseat 10-20° C. and the mixture is stirred for 60 min at 20° C. After cooling to 0° C. 60 ml 62percent hydrobromic acid areadded dropwise while the temperature does not exceed 20° C. After 40 min stirring the reaction mixture is stirred into1150 ml isopropanol at 20° C. and cooled to 10° C. The crude product is filtered off, washed with 70 ml cold isopropanoland dried in vacuo. Yield 61.5 g reddish-brown crystals, TLC corresponds to comparison. The crude product is dissolvedin 615 ml methanol with 6.15 g activated charcoal at reflux temperature and filtered. Then 570 ml methanol are distilledoff and the solution is cooled to 10° C. The crystals are filtered off, washed with 35 ml cold methanol and dried. Yield40.9 g whitish-beige crystals, TLC corresponds to comparison. The crystals thus obtained are dissolved in 94 ml waterwith 2.2 g activated charcoal at 80° C. and filtered, and then washed with 24 ml water. After cooling to 15° C. thetiotropium bromide monohydrate which has crystallised out is filtered off, washed with 25 ml water and 35 ml acetoneand dried. Yield 28.6 g (48percent based on the scopine methobromide used).Stage 1:With chloro-trimethyl-silane, 1,1'-carbonyldiimidazole in tetrahydrofuran, DMF (N,N-dimethyl-formamide),Time= 1.5h, T= 0 - 20 °CStage 2:in tetrahydrofuran, DMF (N,N-dimethyl-formamide), Time= 1h, T= 10 - 20 °CStage 3:With potassium tert-butylate, hydrogen bromide, Product distribution / selectivity, more than 3 stagesPatent; Boehringer Ingelheim Pharma GmbH and Co., KG; US2006/47120; (2006); (A1) EnglishView in Reaxys48 %8:5.43 g (50 mmol) chlorotrimethylsilane are added dropwise at 20-30° C. to a solution of 13.1 g (50 mmol) sodiumdithienylglycolate in 25 ml tetrahydrofuran. After 60 min stirring 8.1 g (50 mmol) carbonyldiimidazole and after another30 min 10.01 g (40 mmol) scopine methobromide are added and the mixture is stirred for a further 30 min. Then asolution of 2.60 g (38 mmol) imidazole and 1.65 g (38 mmol) sodium hydride (55percent) in 25 ml dimethylformamideis added dropwise at 20° C. and the mixture is stirred for 1 h at 20° C. After cooling to 0° C. 20 ml 62percent hydrobromicacid are added dropwise while the temperature does not exceed 20° C. After 40 min stirring the reaction mixture isstirred into 350 ml isopropanol at 20° C. and cooled to 10° C. The crude product is filtered off, washed with 50 ml coldisopropanol and dried in vacuo. Yield 18.9 g reddish-brown crystals, TLC corresponds to the comparison. The crudeproduct is dissolved in 100 ml methanol with 2.2 g activated charcoal at reflux temperature and filtered. Then the solutionis evaporated down to 30 ml and cooled to 3° C. The crystals are filtered off, washed with 5 ml cold methanol and dried.Yield 12.1 g whitish-beige crystals, TLC corresponds to the comparison. The crystals thus obtained are dissolved in28 ml water with 1.2 g activated charcoal at 80° C. and filtered. After cooling to 15° C. the tiotropium bromide mono-hydrate which has crystallised out is filtered off and dried. Yield 9.4 g (48percent based on the scopine methobromideused).Stage 1:With chloro-trimethyl-silane, 1,1'-carbonyldiimidazole in tetrahydrofuran, Time= 1.5h, T= 20 - 30 °CStage 2:With 1H-imidazole, sodium hydride in tetrahydrofuran, DMF (N,N-dimethyl-formamide), Time= 1.5h, T= 20°CStage 3:With hydrogen bromide in tetrahydrofuran, DMF (N,N-dimethyl-formamide), isopropyl alcohol, Time=0.666667h, T= 0 - 20 °C , Product distribution / selectivityPatent; Boehringer Ingelheim Pharma GmbH and Co., KG; US2006/47120; (2006); (A1) EnglishView in Reaxys。

立必复(甲磺酸多拉司琼注射液)商品名称：立必复通用名称：甲磺酸多拉司琼注射液主要成份：甲磺酸多拉司琼化学名称：1H-吲哚-3-羧酸，八氢-3-氧-2，6-亚甲基-2H-喹嗪-8-（2α，6α，8α，9αβ）-单甲烷磺酸盐一水合物。

结构式：分子本品适用于肿瘤治疗药物引起的恶心或呕吐，也可用于预防和治疗手术后的恶心或用法：甲磺酸多拉司琼注射液可以100mg/30秒的速度快速静注或用相容的注射溶媒（0.9%氯化钠注射液或5%葡萄糖注射液）稀释至50ml输注15分钟以上。

稀释后的溶液在正常光照条件下室温24小时或冷藏48小时内稳定。

甲磺酸多拉司琼注射液不能与其它药物混合使用，输注前后要冲洗输液通道。

推荐剂量： 1.预防肿瘤化疗引起的恶心和呕吐成人：化疗前30分钟静注单剂量1.8mg/kg甲磺酸多拉司琼注射液；或者大多数患者可以使用固定剂量100mg，静注30秒以上。

儿童患者：2-16岁儿童患者建议在化疗前30分钟静注单剂量1.8mg/kg甲磺酸多拉司琼注射液，最大量不超过100mg。

2岁以下儿童用药的安全性和疗效尚未确立。

甲磺酸多拉司琼注射液与苹果汁或苹果-葡萄汁混合后可用于儿童患者口服，2-16岁儿童患者推荐口服剂量是1.8mg/kg，最大量不超过100mg，在化疗前1小时内口服。

稀释后室温下可以保存2小时。

老年患者、肾功能衰竭患者或肝功能障碍患者：无需调整剂量。

2.预防或治疗手术后恶心和/或呕吐成人：外科手术麻醉停止前约15分钟（预防）或刚出现恶心、呕吐时（治疗）静注单剂量甲磺酸多拉司琼注射液12.5mg。

儿童患者：外科手术麻醉停止15分钟或刚出现恶心、呕吐时，2-16岁儿童静注单剂量甲磺酸多拉司琼注射液0.35mg/kg，最大量不超过12.5mg。

2岁以下儿童用药的安全性和疗效尚未确立。

甲磺酸多拉司琼注射液与苹果汁或苹果-葡萄汁混合后可用于儿童患者口服，2-16岁儿童患者推荐口服剂量是1.2mg/kg，最大量不超过100mg，在术前2小时内口服。

酸醋戈那瑞林
戈那瑞林，Gonadorelin
Acetate，为人工合成的促性腺激素释放素，属肽类化合物，为十肽。

用于诊断下丘脑—腺垂体—性腺功能障碍，可根据其中促性腺激素和性激素水平变化进行。

产品名称：醋酸戈那瑞林
英文名称：Gonadorelin Acetate
中文别名：高乐肽；促黄体激素释放激素；促黄体激素释放因子；促黄体生成素释放激素；促黄体生成素释放素；促性激素释放素；促性释放素
英文别名：Crylocur、Crytocur、Furtiral、GonadotropinReleasingHormone、Lutei CAS号：34973-08-5
序列：pGlu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH2
分子式：C55H75N17O13.C2H4O2
分子量：1242.36
分子结构：
（台州保隆化工）
储存环境：2～8℃。

【瑞莫杜林药品名称】通用名称：曲前列尼尔注射液商品名称：瑞莫杜林（Remodulin）英文名陈：Treprostinil Injection【瑞莫杜林成分】瑞莫杜林主要成分曲前列尼尔。

化学名称：[[1R,2R,3aS,9aS）-2,3,3a，4,9,9a-六氢-2-羟基-1-[（3S）-3-羟基辛烷基]-1H-苯并[f]茚-5-基]氧基]乙酸分子式：C23H33NaO5分子量：390.52辅料：枸橼酸钠二水合物、盐酸、间甲酚、氢氧化钠、氯化钠、注射用水。

【瑞莫杜林性状】瑞莫杜林为无色至微黄色的澄明液体。

【瑞莫杜林适应症】瑞莫杜林用于治疗肺动脉高压（PAH,WHO分类1），以减轻运动引起的相关症状。

在建立瑞莫杜林疗效的研究中，研究受试者包括NYHA 功能分级II~IV级的原发性和遗传性肺动脉高压（58）、与先天性体肺循环分流相关的肺动脉高压（23）以及与结缔组织疾病相关的肺动脉高压（19）。

【瑞莫杜林规格】20ml：20mg【瑞莫杜林用法用量】瑞莫杜林用20ml玻璃瓶包装，含有20mg曲前列尼尔（1mg/ml）。

瑞莫杜林输注前需用注射用水或0.9NaCl注射液稀释。

瑞莫杜林的给药方式为皮下或静脉注射给药。

首次接受前列环素输注治疗患者的初始剂量瑞莫杜林只能连续皮下（SC）或静脉（IV）输注。

皮下输注是给药路径。

但是，如果因为注射部位严重疼痛或反应而不能耐受皮下给药，也可经中心静脉导管给药。

初始输注速率为1.25ng/kg/min。

如果由于全身效应不能耐受初始剂量，应将注射速率降低至0.625ng/kg/min。

剂量调整长期剂量调整的目标是确定曲前列尼尔的剂量，使其可改善肺动脉高压症状，同时减少瑞莫杜林的其他药理效应（头痛、恶心、呕吐、坐立不安、焦虑以及输注部位疼痛或反应）。

根据临床疗效进行剂量调整。

在治疗的前四周，输注速率的增加值为每周1.25ng/kg/min，之后为每周2.5ng/kg/min。

复方匹可硫酸钠质量标准复方匹可硫酸钠是一种复方制剂，其质量标准可能因不同的生产厂家和剂型而有所差异。

以复方匹可硫酸钠颗粒为例，其质量标准如下：- 性状：本品为白色至微黄色颗粒或粉末，略有橙子香味。

- 适应症：用于结肠镜检查、X射线检查前的肠道清洁准备。

- 用法用量：口服。

将本品一袋倒入150毫升的冷水中，搅拌2~3分钟使之溶解，放凉后服用。

每次一袋，共两次。

- 成份：本品为复方制剂，其组份为：每袋含匹可硫酸钠（C18H13NNa2O8S2·H2O）10mg、氧化镁（MgO）3.5g和枸橼酸（C6H8O7）12.0g。

- 药理毒理：复方匹可硫酸钠颗粒是匹可硫酸钠和枸橼酸镁组成的复方制剂。

匹可硫酸钠直接作用于结肠粘膜刺激结肠蠕动；氧化镁和枸橼酸反应生成枸橼酸镁溶液，为渗透性泻药，可增加肠内的水分。

匹可硫酸钠和枸橼酸镁产生双效泻药的效果，当摄入额外液体时产生水样腹泻。

- 毒理作用：- 遗传毒性：匹可硫酸钠Ames试验、小鼠淋巴瘤试验和骨髓瘤细胞基因突变试验结果均为阴性。

- 生殖毒性：大鼠经口给予匹可硫酸钠达100mg/kg，未见对雄性和雌性动物生育力的明显影响。

兔经口给予匹可硫酸钠1000mg/kg/天，可见胚胎毒性，其安全剂量相当于预期人用剂量的3000-30000倍。

- 致突变性：无相关数据。

- 不良反应：有个别轻微的可逆性的回肠阿弗他溃疡的报告。

腹泻和大便失禁是本品的主要不良反应。

上市后有个别严重腹泻的报告。

有低钠血症伴或不伴惊厥的报告。

在癫痫患者中，有癫痫发作/大发作不伴有低钠血症的个别报告。

有高镁血症的报告。

有类过敏反应的个别报告。

- 禁忌：本品禁用于以下情况：对本品任一组分过敏，充血性心力衰竭，胃潴留，消化性溃疡，中毒性结肠炎，中毒性巨结肠，肠梗阻，恶心、呕吐，进行急诊腹部手术如急性阑尾炎，已知或疑似胃肠道梗阻或穿孔，严重脱水，横纹肌溶解症，高镁血症，活动性炎症性肠病。

肾功能平重损伤（肌酐清除率低于30mL/min）者可能发生镁蓄积。

依来曲普坦 Eletriptan【通用名】：依来曲普坦 【中文化学名】：5-［2-（苯磺酰基）乙基］-3-［1-甲基吡咯烷-2(R)-基甲基］-1H-吲哚 【英文化学名】：5-［2-（benzenesulfonyl ）ethyl ］-3-［1-methylpyrrolidin-2(R)-ylmethy ］-1H-indole【商品名】：Repax 【异名（别名）】：马来酸阿莫曲普坦、阿莫曲普坦、阿莫曲坦、依立曲坦、依西曲坦 【缩写】：依立曲坦、依西曲坦 【华学文摘号】：CA 117: 171215n 【CAS 登陆号】：［143322-58-1］ 【分子式】：C 22H 26N 2O 2S 【分子量】：382.53 【结构式】：HNNS O O【专利号】：WO 9206973, US 5545644, US 5607951 【专利到期年份】： 【原研机构】：美国Pfizer 公司 【首次上市时间】：2001年5月 【首次上市国家】：澳大利亚、丹麦、挪威、瑞典、瑞士 【物理与化学性质】：白色或淡灰白色粉末，易溶于水，水溶度为1.18*10^-3mg/mL 【主要作用与功效】：治疗偏头痛 【常用剂型】：薄膜包衣片：每片20mg 或40mg 。

【注意事项】：对本品任何成分过敏者禁用本品；严重肝肾受损者、高血压未控制者、冠心病、周围血管病、有脑血管意外（CV A ）或暂时性局部缺血发作（TIA ）史的患者禁用。

轻中度肾脏受损者及怀孕、哺乳期妇女、儿童需慎用。

本品不可与麦角胺、麦角胺衍生物（包括美西麦角）或其他5-HT 1受体激动剂同时使用。

本品可增加CYP3A4抑制剂的血药浓度，包括红霉素、维拉帕米、酮康唑、依曲康唑、萘法唑酮、醋竹桃霉素、克拉霉素、利托那韦及那非那韦，因而至少72小时内不可与之合用。

【合成路线】： 路线一：N BrHNLiAlH THF,refluxPd(OAc)2,(o-tol yl)3P Et 3N,DMF,refluxSOOSOSO路线二：NBrHNLiAlH THF,refluxPd(OAc)2,(o-tolyl)3P Et 3N,DMF,refluxSOSOw is acid,CH Cl 2Ao 2O,El 3N,DMF SOK 2CO 3,MeOH路线三：NH.HClOH KOH,CbzCl,HO,tolueneNNCbzOMeOOBrMg THF,O ON OCbzO ONMeHO 2CCO 2HDlbenzoyl-L-tartarlc acldO2HeletrlptanPhO 2SN N OO H H(【参考文献】：［1］ 李晓东. 偏头痛治疗药依来曲普坦（eletriptan ）.世界临床药物，2003,24（2）：122-123.［2］ 刘萍，边强. Replax 中国新药杂志，2004,13（1）：79-80.［3］ 郑红云.治疗偏头痛的新药Eletriptan 。

王婕 913103860408NEULASTA（PEGFILGRASTIM）|培非格司亭注射液1.Introduction(简介)【产地英文商品名】:NEULASTA－6mg/0.6ml/Syringe【原产地英文药品名】:PEGFILGRASTIM【中文参考商品译名】:纽拉思塔-6毫克/0.6毫升/支【中文参考药品译名】:培非格司亭【生产厂家中文参考译名】:安进【生产厂家英文名】:Amgen, IncAmgen Announces Novel Drugs for Antitumor Chemotherapy Side Effects of FGT (TM) (pegfilgrastim), a drug developed by the US Food and Drug Administration (FDA), has been approved by the US Food and Drug Administration (FDA) Approval. Amphetamycin, the chief executive of Amgen, says that pemetrexedin will make it easier for healthcare workers to prevent chemotherapy-induced neutropenia and its serious complications.The third drug approved by Amgen in the past six months will significantly improve the prognosis of chemotherapy patients and is expected to enter the market in early April.BUSINESS WIRE 2002年2月1日美国加州THOUSAND OAKS消息，安进公司宣布抗肿瘤化疗副作用新药培非格司亭(TM) (pegfilgrastim)通过美国食品与药品管理局（FDA）的审批。

SJL01 MultiVu - C_MSDCHEM_1_DATA_SJL1、 CAS Number:64-17-5 基本信息中文名: 乙醇;酒精;无水乙醇英文名: Etanol分子结构:分子式: C 2H 6O分子量: 46.07 2、 CAS Number:562-74-3 基本信息中文名: 4-萜烯醇;4-甲基-1-(1-甲基乙基)-3-环己烯-1-醇英文名: Terpinen-4-ol分子结构:分子式: C 10H 18O分子量: 154.253、 CAS Number:16728-99-7 基本信息英文名: Naphthalene,1,2,3,4,4a,7-hexahydro-1,6-dimethyl-4-(1-methylethyl)- 分子结构:分子式: C 15H 24分子量: 204.351064、 CAS Number:17066-67-0 基本信息英文名: Naphthalene,decahydro-4a-methyl-1-methylene-7-(1-methylethenyl)-,(4aR,7R,8aS)-分子结构:分子式: C 15H 24分子量: 204.35115、 CAS Number:473-13-2 基本信息英文名: Naphthalene,1,2,3,4,4a,5,6,8a-octahydro-4a,8-dimethyl-2-(1-methylethenyl)-, (2R,4aR,8aR)-分子结构:分子式:C 15H 24分子量: 204.35116、 CAS Number:25360-09-2 基本信息中文名: 叔十六硫醇英文名: tert-Hexadecanethiol分子结构:分子式: C16H34S分子量: 258.5067、CAS Number:19780-11-1 基本信息中文名: 十二烯基丁二酸酐英文名: 2,5-Furandione,3-(2-dodecen-1-yl)dihydro- 分子结构:分子式: C16H26O3分子量: 266.37588、Name: (-)-SpathulenolFormula: C15H24OMW: 220 CAS#: 77171-55-29、CAS Number:661-19-8 基本信息中文名: 山嵛醇;1-二十二醇英文名: 1-Docosanol分子结构:分子式: C22H46O分子量: 326.6010、CAS Number:25360-09-2 基本信息中文名: 叔十六硫醇英文名: tert-Hexadecanethiol分子结构:分子式: C16H34S分子量: 258.50611、Name: 2,5-Furandione, 3-dodecyl Formula: C16H26O3MW: 266 CAS#: 59426-46-912、CAS Number:6750-34-1 基本信息英文名: 1-Dodecanol,3,7,11-trimethyl- 分子结构:分子式: C15H32O分子量: 22813、CAS Number:56847-02-0 基本信息英文名: Methyl 8,11,14-docosatrienoate 分子结构:分子式: C23H40O214、CAS Number:16714-85-5 基本信息英文名: (E)-10-Heptadecen-8-ynoic acid methyl ester 分子结构:分子式: C18H30O2分子量: 278.429615、CAS Number:2490-48-4 基本信息英文名: 1-Hexadecanol,2-methyl-分子结构:分子式: C17H36O分子量: 256.467116、Name: Urea, 1-(2-methylphenyl)-3-propyl Formula: C11H16N2OMW: 192 CAS#: 13143-12-917、Name: Dihydrocoumarin, 5,7,8-trimethyl Formula: C12H14O2MW: 190 CAS#: 40614-33-3。

【对乙酰氨基酚】
结构式：
日文名：アセトアミノフェン
英文名：Acetaminophen
或Paracetamol
解离常数（25℃）：pKa = 9.5（针对苯酚基团上的羟基）
在各溶出介质中的溶解度（37℃）：pH1.2：14.9mg/ml pH4.0：15.3mg/ml
pH 6.8：15.4mg/ml 水：15.8mg/ml
在各溶出介质中的稳定性：
水：未测定。

在各pH值溶出介质中：未测定。

光：未测定。

《四条标准溶出曲线》
溶出度试验条件：桨板法/50转、溶出介质中不添加表面活性剂。

< 1g:200mg规格颗粒剂>
< 200mg规格片剂>
《质量标准》
取本品1包（或1片），照溶出度测定法（桨板法），以水900ml为溶剂，转速为每分钟50转，依法操作，经30分钟（片剂15分钟）时，取溶液适量，弃去至少10ml初滤液，精密量取续滤液3ml，置100ml量瓶中，加水稀释至刻度，摇匀，作为供试品溶液。

另精密称取经105℃干燥2小时的对照品15mg，置100ml量瓶中，加甲醇2ml使溶解，再加水稀释至刻度，摇匀，精密量取1ml，置25ml量瓶中，加水稀释至刻度，摇匀，作为对照品溶液。

取上述两种溶液照紫外-可见分光光度法，在243nm的波长处测定吸光度，计算出每包（片）溶出量，限度为标示量的80%，应符合规定。

2 羟戊基苯甲酸钾类别：化学药品第1.1类适应症：缺血性脑血管病剂型：片剂（规格100mg/片）和冻干粉针（规格50mg/支）进度：已获临床批件， I期临床试验进行中。

知识产权: 已经申请国内国际化合物专利，中国、俄罗斯和韩国已经获得专利授, 欧洲、美国、日本、巴西、加拿大、印度、印尼和以色列专利正在实审阶段。

中国ZL01109795.7（2006.3.1）俄罗斯2305092（2007.4.13）韩国756470 (2004.12.17)转让方式：国内市场已转让，现寻求国际技术转让研究背景：脑血管疾病（脑卒中）为脑血管阻塞或破裂引起脑部血流受阻所致病症，分缺血性脑卒中和出血性脑卒中。

据报道我国城镇和乡村人群抽样调查结果表明，年发病率分别为219/10万和185/10万，死亡率为116/10万和141.8/10万，且趋年轻化。

我国每年新发脑卒中病人约150~200万人，其中缺血性脑卒中约占脑卒中病例的60~80%。

1992年我国城乡人口死亡原因中，脑卒中均排在第二位，占死亡总人数的21.13%和16.18%。

北京地区缺血性脑卒中的比例1999年达81.6%。

我国死于脑血管病多于死于心脏病及癌症，位于三大死因之首。

脑卒中不但以高发病率、高死亡率、高致残率危害人民健康，而且在存活下来的占80%的中风患者中，仅有10%左右能完全恢复正常功能，绝大多数患者都留有偏瘫，失语等后遗症，从而对社会及家庭造成极严重的负担。

其它国家的状况也大致相似。

因此对脑血管病的防治为全社会所关注。

各国药物学家和医疗专家及各方力量（政府、社会团体）将研发防治脑血管病的药物视为迫切使命，但国内外尚无理想的治疗药物。

我们在前期研究抗轻、中度急性缺血性脑卒中新药消旋3-正丁基苯酞（dl-NBP，商品名“恩必普”）基础上，利用前药原理深入研发出具有自主知识产权的前药消旋2-（α-羟基戊基）苯甲酸钾（dl-PHPB）原料药、片剂和冻干剂，以克服丁苯酞存在的不足，增加治疗急性缺血性脑血管病药物的新品种、扩大适应症，适用于从轻度至重度急性缺血性脑血管病患者的治疗。