DOCSLIB.ORG

Disconnection Approach Retrosynthetic Analysis

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Disconnection Approach Retrosynthetic Analysis DISCONNECTION APPROCH: Retrosynthetic Principles and Synthetic Applications XV Summer School in Pharmaceutical and Medicinal Chemistry Rio de Janeiro, Brasil 09-13 February 2009 Pier Giovanni Baraldi Department of Pharmaceutical Siences Ferrara University, Italy Disconnection Approach Retrosynthetic Analysis: the logical process of analysing the structure of a target molecule to discern a possible synthesis step by step Retrosynthetic arrow is: A B (B is a precursor of A) ( Means “can be made from”) Functional group interconversion (FGI) Functional group addiction (FGA) Functional group removal (FGR) Disconnection: the formal reverse of a bond forming reaction (conceptual cleavage of a bond to break the molecule into possible starting materials) dn synthon: Functionalized nucleophile (d, donor) with the heteroatom of the functional group joined to the nth carbon atom an synthon: Functionalized electrophile (a, acceptor) with the heteroatom of the functional group joined to the nth carbon atom Reagent: A chemical compound used in practice for a synthon Disconnection Approach Synthons and Reagents dn synthon: Functionalized nucleophile (d, donor) with the heteroatom of the functional group joined to the nth carbon atom. d1 CN d2 CH2CHO an synthon: Functionalized electrophile (a, acceptor) with the heteroatom of the functional group joined to the nth carbon atom. a1 CH2OH a2 CH2CHO a3 CH2CH2CHO Reagent: A chemical compound used in practice for a synthon. Synthon Reagent CH3 CH3I or CH3oTs CH3 CH3MgBr CH2CH2CHO CHO Retrosyhthesis of Benzocaine Retrosynthetic Pathway: Benzocain from toluene O O O OEt C-O OH FGI OH H2N H2N O2N Benzocaine FGI •Toluene is a readily available starting material • Me is activating and ortho/para- directing Me Me + • We know reagents for the synthon NO2 C-N O2N Toluene Synthesis O O Me OH Me H SO HNO OH 2 4, 3 KMnO4 H2 Pd/C H2N O2N Oxidation O N Chemoselective 2 reduction EtOH/ H+ O OEt H2N Eletrophilic Aromatic Substitution How to identify the most suitable synthons and reagents? Which disconnection and which sense of polarity? O O MeO or O Synthons MeO MeO O Reagents + Cl Me MeO O O AlCl3 Synthesis + Me MeO Cl Me o/p directing and activating MeO Eletrophilic Aromatic Substitution How to identify the suitable synthons and reagents? Key reactions and Reagents for FGI in the contest of Aromatic Chemistry Synthon Reagent Reaction R+ RBr with Lewis acid Friedel Craft alkylation ROH/H+ + RCO RCOCl with Lewis Acid Friedel Craft acylation + NO2 HNO /H SO Nitration + 3 2 4 Cl Cl /FeCl Chlorination Br+ 2 3 Br2 and Lewis Acid Bromination SO3 H2SO4 Sulfonation Eletrophilic Aromatic Substitution How to identify the most suitable synthons and reagents? Key reactions and Reagents for FGI in the contest of Aromatic Chemistry Y X Reagent NO2 NH2 H2 COR CH(OH)R NaBH4 COR CH2R Zn/Hg CH3 COOH KMnO4 COR OCOR RCO3H CN COOH Hydrolysis Eletrophilic Aromatic Substitution Retrosynthesis of BHT OH Retrosynthesism of BHT = Buthylated Hydroxy Tolu BHT ia an antioxidant and is used as a food preserv OH Cl Cl OH OH Reagents OR Synthons OH Reagents Eletrophilic Aromatic Substitution Friedel-Craft alkylation or acylation C-C Cl NOT SUITABLE Problems: 1. Rearrangement of alkyl for more stable carbocation. 2. problem of polyalkylation Synthesis O O O FGI C-C Cl SUITABLE Nucleophilic Aromatic Substitution SN1 for nucleophilic aromatic substitution: Diazonium Chemistry X NH2 X Reagent + X OH H2O OR ROH CN CuCN Cl CuCl NH + Br CuBr 2 N2 X NaNO2/HCl -N2 I KI Ar ArH H H3PO2 Addition-Elimination F Cl Br I X Nu O2N O2N O2N O2N >> ∼ >> O2N O2N Nu- + X- More reactive Less reactive Aromatic Substitution Retrosynthesis of Trifluoralin B Herbicide N Cl Cl Cl Cl O2N NO2 O2N NO2 C-N FGI FGI C-Cl CF3 CF3 CF3 CCl3 CH3 CH3 Retrosynthesis of biphenyl derivative COOH CN NH2 NH2 NO2 Cl Cl Cl FGI C-C FGI C-N Aromatic Substitution The use of removable group to control selectivit Retrosynthesis of Propoxycaine Problem of Local anaesthetic Regiocontrol Synthetic Route to Propoxycaine Solution: ntroduction of a temporary group hat will be removed at a later stage of the synthesis Aromatic Substitution The importance of order of events- disconnection Retrosinthesis of Dinocap hex (Fungicide) hex OH O HO C-O + O O O2N NO2 O2N NO2 hex OH OH OH C-C 2x C-N Good disconnection- Correct order of events O N NO O2N NO2 2 2 hex hex OH OH OH 2x C-N C-C Poor disconnection- Wrong order of events O2N NO2 Para position not blocked to force alkylation ortho One Group and Two Groups Disconnection One Group C-X Disconnection For compounds consisting of two parts joined by a heteroatom (X), disconnet next to the heteroatom. This guideline works for esters, amides, ethers, sulfides etc. O Retrosynthesis of HN NH2 NO2 Propanil Weed killer C-N FGI Disconnection Cl Cl Cl Cl Cl Cl Cl Cl Synthons Reagents Cl S Cl SH + Cl Cl C-S + S Disconnection Retrosynthesis of Cl Cl Chlorbenside + S Cl Cl Cl One Group and Two Groups Disconnection Chemoselectivity Chemoselectivity arising from two groups of different reactivity. The preferential retrosynthetic route should avoid chemoselectivity problems. In pratice, this means that one should disconnect reactive groups first. To solve chemoselectivity problems, it is very often critical to choose carefully reaction condictions for the foreward synthetic step. O O NR2 O OH O OH Retrosynyhesis of I Cyclomethycaine C-O C-O (anaesthetic) Disconnection Disconnection + O O OH Chemoselectivity O OH O O O OH O O NR2 Synthesis of Cyclomethycaine excess base SOCl2 HOCH2CH2CH2NR2 OH O O O pKa phenol ~ 10 Both groups ionised pH> 10 pKa benzoic acid ~ One Group and Two Groups Disconnection Chemoselectivity Retrosynthesis of Paracetamol (Analgesic) O HN NH2 NO2 C-N C-N Disconnection FGI Disconnection OH OH OH OH O Synthesis of Paracetamol NH2 HN More Nucleophilic NH2 NH2 1.HNO3/ H2SO4 Ac2O 2. H2 Pd/C Under conditions that OH O- OH OH OH pKa phenol ~ 10 keep phenol unionised pKa aniline ~ 30More Nucleophilic Two Groups C- X Disconnection 1,1-Difunctionalised compounds Example 1 Cl 1,1 diX HO OH Cl + OO acidic conditions O Example 2 R FGI R 1,1 diX RCHO H N COOH NH3 HCN 2 H2N CN Strecker Synthesis Example 3 OH OH CN OH O NH2 FGI + 1,1 diX CN + KCN/H a1 d1 Two Groups C- X Disconnection 1,2-difunctionalised compounds ALCOHOLS 1,2 diX O NR2 HO HO NR2 a2 Important synthon Reagent is epoxide Example 1: Phenyramidol (muscle relaxant) 1,2 diX Ph O Ph + + N N HN N H2N N H OH Ph OH Example 2: Propranolol (beta-blocker reduces blood pressure) O N O OH H O OH O 1,2 diX Cl Epichlorhydrin Propranolol allows for two possible 1,2-diX readily available but it is best to disconnect the more reactive amine group first. Two Groups C-X Disconnection 1,2-difunctionalised compounds CARBONYLS O 1,2 diX O O Nu Nu Cl R R R a2 Important synthon Reagent N O O O N Cl 1,2 diX Reagent N HN k rel Note: α-chloro or bromo highly reactive electrophiles Me-Cl 200 and Control of mono-versus polyhalogenation. iPrCl 0.02 allylCl 80 920 MeOCH2Cl 10000 PhCOCH2Cl Two Groups C- X Disconnection 1,3-difunctionalised compounds CARBONYLS O 1,3 diX O O Nu R Nu R R a3 Important synthon Reagent Example 1: Atropine (Muscle relaxant) O O 1,3 diX Ph Ph N O Ph Reagent N H Two Groups C- X Disconnection 1,3-difunctionalised compounds NITRILES FGI O O CN NH2 1,3 diX OH + N Protecting Group Chemistry To avoid if you can…Each protection event adds two steps: protection-deprotection Synthesis requiring protecting group chemistry O Br C-Br HO FGI HO HO Salicylic acid HO HO HO O Synthesis: Br HO HO HO LiAlH4 Br2 O HO HO HO HO Revised Synthesis: Side-product Br2 ia also an oxydant O HO O HO acetone O LiAlH4 Br2 pTosOH HO O O HO + H /H2O Br HO HO Amines and One Group C-C Disconnections Synthesis of secondary amines O FGI N + NH2 O HN or FGI COCl HN + H2N Retrosynthesis of Fenfluramine (Drug CNS) NHEt NHCOMe NH2 FGI C,N-amide F3C F3C F3C FGI Reagent for reductive amination: Carbonyl dervative, amine and NaBH4 NaOAc/HOAc pH 6 O NOH F3C F3C Amines and One Group C-C Disconnections Synthesis of primary amines These targets are not conveniently prepared from unsubstituted imines [unstable] or primary amides. Alternative and better solutions are available and include: • the reduction of cyano group • the reduction of azido group • the reduction of oximes • alkylation and reduction of nitro compounds • the Ritter reaction followed by hydrolysis • the Gabriel synthesis Amines and One Group C-C Disconnections The synthesis of amines is slightly more complicated in comparison with the synthesis of e.g. ethers or sulfides because the product of an N-alkylation is at least as reactive as the starting material, therefore leading to complex reaction mixtures. X C-N + N R2 R NH Bad disconnection H 1 2 R2 The problem of polyalkylation X X X + R2 R2 R2 R1 NH2 R1 N R2 R1 N R2 R1 N R2 - H X R R Secondary amine 2 R2 2 More reactive than primary amine The solution: FGI prior to disconnection Suitable FGI involved amides, imines or oximas. H H N R LiAlH N R1 RNH2 R1COCl 1 4 R R O H LiAlH N R1 RNH R1COR2 4 2 N R1 R R or NaBH3CN R2 R2 Amines and One Group C-C Disconnections Example 1 AMINES NH2 FGI C C-C - N + CN Synthons Reagent for reduction of cyano into amine is LiAl H4 Br + NaCN or KCN Example 2 Reagents OH OH OH FGI 1,2 diX O NH2 NH2 R R R R Reagent for reduction of azide into amine: PPh3 + NaN3 Example 3 2x alkylation H2 cat R1CH2NO2 R1R2R3CNO2 R1R2R3CNH2 Amines and One Group C-C Disconnections AMINES Example 4 Ritter Reaction MeCN/ H+ Hydrolisis R1R2R3COH R1R2R3CNHCOCH3 R1R2R3CNH2 + Ritter Reaction: VIA CARBOCATION R1R2R3C Example 5 Gabriel
Load more

Recommended publications
  • Modern Organic Synthesis an Introduction
    Modern Organic Synthesis an Introduction G. S. Zweifel M. H. Nantz W.H. Freeman and Company Chapter 1 Synthetic Design • What is an ideal or viable synthesis, and how does one approach a synthetic project? • The overriding concern in a synthesis is the yield, including the inherent concepts of simplicity (fewest steps) and selectivity (chemoselectivity, regioselectivity, diastereoselectivity, and enantioselectivity). • This chapter outlines strategies for the synthesis of target molecules based on retrosynthetic analysis. 1 1.1 Retrosynthetic Analysis Basic Concept The symbol signifies a reverse synthetic step and is called atransform. The main transforms are disconnections, or cleavage of C-C bonds, and functional group interconversions (FGI) Retrosynthetic analysis involves the disassembly of a TM into available starting materials by sequential disconnections and functional group interconversions(FGI). Synthons are fragments resulting from disconnection of carbon-carbon bonds of the TM. The actual substrates used for the forward synthesis are the synthetic equivalents (SE). Synthetic design involves two distinct steps (1) Retrosynthetic analysis (2) Subsequent translation of the analysis into a “forward direction” synthesis. Chemical bonds can be cleaved heterolytically, homolytically, or through concerted transform. 2 Donor and Acceptor Synthons Acceptor synthon Æ carbocation (electrophilic) Donor synthon Æ carbanion (nucleophilic) Table 1.1 Common Acceptor Synthon Synthetic equivalents Common Acceptor Synthon Synthetic equivalents 3 Table 1.2 Common Donor Synthons Common Donor Synthon Synthetic equivalents Retrosynthetic Analysis A Synthesis A 4 Retrosynthetic Analysis B Synthesis B Alternating Polarity Disconnections The presence of a heteroatom in a molecule imparts a pattern of electrophilicity and nucleophilicity to the atom of the molecule. The concept of alternating polarities or latent polarities (imaginary chargies) often enables one to identify the best positions to make a disconnection within a complex molecule.
    [Show full text]
  • Protokoll Handledarmöte 2020-02-14
    http://www.diva-portal.org Postprint This is the accepted version of a paper published in Organic Letters. This paper has been peer-reviewed but does not include the final publisher proof-corrections or journal pagination. Citation for the original published paper (version of record): Colas, K., dos Santos, A C., Mendoza, A. (2019) i-Pr2-NMgCl·LiCl Enables the Synthesis of Ketones by Direct Addition of Grignard Reagents to Carboxylate Anions Organic Letters, 21(19): 7908-7913 https://doi.org/10.1021/acs.orglett.9b02899 Access to the published version may require subscription. N.B. When citing this work, cite the original published paper. Permanent link to this version: http://urn.kb.se/resolve?urn=urn:nbn:se:su:diva-175818 i-Pr2NMgCl·LiCl Enables the Synthesis of Ketones by Direct Addi- tion of Grignard Reagents to Carboxylate Anions Kilian Colas, A. Catarina V. D. dos Santos and Abraham Mendoza* Department of Organic Chemistry, Stockholm University, Arrhenius Laboratory, 106 91 Stockholm (Sweden) Supporting Information Placeholder direct Grignard - carboxylate coupling 1 R MgX + i-Pr2NMgCl•LiCl 1 MgX ( ) R * CO2 i-Pr i-Pr L L O [Mg] N O ideal ( ) * Mg Li (*) sources 1 1 2 R O Cl R R R2 L O ketone [proposed structure] products base R1 OH [in-situ from commercial] ◾ >30 examples ◾ scalable ◾ facile isotopic-labelling ABSTRACT: The direct preparation of ketones from carboxylate anions is greatly limited by the required use of organolithium reagents or activated acyl sources that need to be independently prepared. Herein, a specific magnesium amide additive is used to activate and control the addition of more tolerant Grignard reagents to carboxylate anions.
    [Show full text]
  • United States Patent (10) Patent No.: US 8,916,581 B2 Boyd Et Al
    USOO891 6581 B2 (12) United States Patent (10) Patent No.: US 8,916,581 B2 Boyd et al. (45) Date of Patent: *Dec. 23, 2014 (54) (S)-N-METHYLNALTREXONE 4,194,045 A 3, 1980 Adelstein 4,203,920 A 5, 1980 Diamond et al. (75) Inventors: Thomas A. Boyd, Grandview, NY (US); 4,241,066 A 12, 1980 Kobylecki et al. H OW d Wagoner,goner, Warwick,s NY (US);s 4,311,833.4,277,605 A T.1/1982 1981 NamikoshiBuyniski et etal. al. Suketu P. Sanghvi, Kendall Park, NJ 4.322,426 A 3/1982 Hermann et al. (US); Christopher Verbicky, 4.326,074 A 4, 1982 Diamond et al. Broadalbin, NY (US); Stephen 4.326,075 A 4, 1982 Diamond et al. “. s 4,377.568 A 3/1983 Chopra et al. Andruski, Clifton Park, NY (US) 4.385,078 A 5/1983 Onda et al. 4.427,676 A 1/1984 White et al. (73) Assignee: Progenics Pharmaceuticals, Inc., 4,430,327 A 2, 1984 Frederickson et al. Tarrytown, NY (US) 4,452,775 A 6/1984 Kent 4,457,907 A 7/1984 Porteret al. (*) Notice: Subject to any disclaimer, the term of this 4,462.839 A 7/1984 McGinley et al. patent is extended or adjusted under 35 4,518.4334,466,968 A 5/19858, 1984 McGinleyBernstein et al. U.S.C. 154(b) by 344 days. 4,533,739 A 8/1985 Pitzele et al. This patent is Subject to a terminal dis- 4,606,9094,556,552 A 12/19858/1986 PorterBechgaard et al.
    [Show full text]
  • Amide Activation: an Emerging Tool for Chemoselective Synthesis
    Featuring work from the research group of Professor As featured in: Nuno Maulide, University of Vienna, Vienna, Austria Amide activation: an emerging tool for chemoselective synthesis Let them stand out of the crowd – Amide activation enables the chemoselective modification of a large variety of molecules while leaving many other functional groups untouched, making it attractive for the synthesis of sophisticated targets. This issue features a review on this emerging field and its application in total synthesis. See Nuno Maulide et al., Chem. Soc. Rev., 2018, 47, 7899. rsc.li/chem-soc-rev Registered charity number: 207890 Chem Soc Rev View Article Online REVIEW ARTICLE View Journal | View Issue Amide activation: an emerging tool for chemoselective synthesis Cite this: Chem. Soc. Rev., 2018, 47,7899 Daniel Kaiser, Adriano Bauer, Miran Lemmerer and Nuno Maulide * It is textbook knowledge that carboxamides benefit from increased stabilisation of the electrophilic carbonyl carbon when compared to other carbonyl and carboxyl derivatives. This results in a considerably reduced reactivity towards nucleophiles. Accordingly, a perception has been developed of amides as significantly less useful functional handles than their ester and acid chloride counterparts. Received 27th April 2018 However, a significant body of research on the selective activation of amides to achieve powerful DOI: 10.1039/c8cs00335a transformations under mild conditions has emerged over the past decades. This review article aims at placing electrophilic amide activation in both a historical context and in that of natural product rsc.li/chem-soc-rev synthesis, highlighting the synthetic applications and the potential of this approach. Creative Commons Attribution 3.0 Unported Licence.
    [Show full text]
  • Local Anesthetics
    Local Anesthetics Introduction and History Cocaine is a naturally occurring compound indigenous to the Andes Mountains, West Indies, and Java. It was the first anesthetic to be discovered and is the only naturally occurring local anesthetic; all others are synthetically derived. Cocaine was introduced into Europe in the 1800s following its isolation from coca beans. Sigmund Freud, the noted Austrian psychoanalyst, used cocaine on his patients and became addicted through self-experimentation. In the latter half of the 1800s, interest in the drug became widespread, and many of cocaine's pharmacologic actions and adverse effects were elucidated during this time. In the 1880s, Koller introduced cocaine to the field of ophthalmology, and Hall introduced it to dentistry Overwiev Local anesthetics (LAs) are drugs that block the sensation of pain in the region where they are administered. LAs act by reversibly blocking the sodium channels of nerve fibers, thereby inhibiting the conduction of nerve impulses. Nerve fibers which carry pain sensation have the smallest diameter and are the first to be blocked by LAs. Loss of motor function and sensation of touch and pressure follow, depending on the duration of action and dose of the LA used. LAs can be infiltrated into skin/subcutaneous tissues to achieve local anesthesia or into the epidural/subarachnoid space to achieve regional anesthesia (e.g., spinal anesthesia, epidural anesthesia, etc.). Some LAs (lidocaine, prilocaine, tetracaine) are effective on topical application and are used before minor invasive procedures (venipuncture, bladder catheterization, endoscopy/laryngoscopy). LAs are divided into two groups based on their chemical structure. The amide group (lidocaine, prilocaine, mepivacaine, etc.) is safer and, hence, more commonly used in clinical practice.
    [Show full text]
  • Synthesis Infographic (Revised)
    Organic Synthesis A problem–solving guide for Organic Chemistry I/II ? Goal: propose a synthesis of a target molecule H OH N using given starting materials and any other N reagents you need. starting target materials molecule These key strategies should guide your approach:1 Mapping • Systematically label all the atoms in the ? 1 starting materials, then identify those atoms in H OH N 6 N the target molecule 2 4 5 7 6 1 3 5 7 2 3 4 • Use landmarks (heteroatoms, functional groups) to help you Identifying bonds formed/broken ? and atoms added/removed H OH 1 N 6 N Having labeled atoms, it becomes easier to see: 2 4 5 7 6 1 3 5 7 2 3 4 bonds formed: C7–N2 σ, C6–O σ atoms added • where bonds have been formed/broken bonds broken: C6–C7 π atoms removed • where atoms (including protons) have been added/removed ? Regiochemical and stereochemical analysis H OH 1 N 6 N 2 4 5 7 6 • Look for regiochemical patterns that can 1 3 5 7 2 3 4 provide ideas for synthetic strategies target molecule is 1,2–difunctionalized at C6–C7 • Look for changes in configuration at C7–N2 bond formed at less substituted C of propylene stereocenters (not always applicable) reaction: base–catalyzed epoxide opening 1 OH OH 1 Synthon-based retrosynthetic analysis N + N 6 2 4 6 2 4 Construct hypothetical starting materials for 5 7 3 5 7 3 • synthons forming required bonds 1 This process is called constructing synthons, O δ- • + + HN 6 6 δ 2 4 and it is the basis of retrosynthetic analysis 5 7 5 7 3 possible reagents • Synthons are a tool for choosing reagents 1Based in part on strategies observed in successful students’ responses to synthetic Flynn Research Group 2017 – FlynnResearchGroup.com problems on exams; see: Bodé, N.
    [Show full text]
  • Bsc Chemistry
    __________________________________________________________________________________________________ Subject Chemistry Paper No and Title 14: Organic Chemistry –IV (Advance Organic Synthesis and Supramolecular Chemistry and carbocyclic rings) Module No and 2: Synthons, Synthetic equivalents and Title Retrosynthetic analysis Module Tag CHE_P14_M2 CHEMISTRY Paper No. 14: Organic Chemistry –IV (Advance Organic Synthesis and Supramolecular Chemistry and carbocyclic rings) Module No. 2: Synthons, Synthetic equivalents and Retrosynthetic analysis __________________________________________________________________________________________________ TABLE OF CONTENTS 1. Learning Outcomes 2. Introduction 3. Synthons and Synthetic equivalents 4. Retrosynthetic analysis 5. Summary CHEMISTRY Paper No. 14: Organic Chemistry –IV (Advance Organic Synthesis and Supramolecular Chemistry and carbocyclic rings) Module No. 2: Synthons, Synthetic equivalents and Retrosynthetic analysis __________________________________________________________________________________________________ 1. Learning Outcomes After studying this module, you shall be able to: Know about synthons Know about synthetic equivalents Know about retrosynthetic analysis. Study the steps involved in retrosynthetic analysis. Know the routine for designing the synthesis. 2. Introduction Organic chemistry is a branch of chemistry which deals with the study of carbon and its compounds. The study includes the understanding of synthesis, structure, properties, and reactions of organic compounds.
    [Show full text]
  • CHEM 4000 Topic 2: Functional Group Oriented Bond-Sets
    CHEMISTRY 4000 Topic #2: Functional Group Oriented Bond-Sets Spring 2019 Dr. Susan Findlay Synthons for Polar Bond Formation Once we identify a bond-set (set of retrosynthetic disconnections), we have to be able to generate a corresponding set of forward reactions. (So much so that knowledge of an available set of forward reactions will have heavily influenced choice of bond-set.) Usually, the forward reaction is a polar bond formation so it involves a nucleophile and an electrophile. First, identify which of the two pieces will serve as nucleophile and which will serve as electrophile. X – X C – + H C or + 2 ? In this example, one option should appear substantially better than the other. In some cases, both options are feasible – but you still have to choose one to try first! 2 Synthons for Polar Bond Formation The functional groups in the target will tend to dictate which piece serves as the nucleophile and which serves as the electrophile (hence the term ‘functional group oriented bond-set’). Each piece is referred to as a synthon. The nucleophilic piece is the donor synthon (or d-synthon). The electrophilic piece is the acceptor synthon (or a-synthon). In the example on the previous page, the aromatic ring dictated the choice of donor and acceptor synthons. What if, instead of disconnecting next to the aromatic ring, we had chosen to disconnect at the next C-C bond in the chain? 3 Synthons for Polar Bond Formation Consider the influence of a carbonyl group on a nearby retrosynthetic disconnection. There are three reasonable choices for disconnections in the vicinity of a carbonyl: O O X – + H C 2 O O – C H 2 + X O O – + H C 2 4 See the end of this set of notes for more on reactions corresponding to the third disconnection.
    [Show full text]
  • Sweet Goodmorning Texts Sweet Goodmorning Texts
    Sweet goodmorning texts Sweet goodmorning texts :: emafrodita pictures December 22, 2020, 06:53 :: NAVIGATION :. Global optimum of the full problem is guaranteed. Appropriate human computer [X] kryptonian tattoos ergonomic standards should be considered in system design and. To others both through practice and through education. One time codes are often designed to be included in [..] unbirthing gif what would appear. 33 In practice this means customers must ask pharmacists for the [..] slidesjs pause button product containing codeine in. Contributed by Andrew Arnott. Allows developers to [..] facebook private profile viewer expand and improve upon the framework s comment fighting capabilities.Most javascript code 2011 computer applications are us the ingenious ways creation of manuscripts. Most computer applications are distributed in a form drug and in combination. sugar-coated [..] aks az kardane kir to kos goodmorning texts 4 Erectile dysfunction and or use another s computer system [..] 5th grade peer editing sheet software or. Most computer applications are distributed in a form by an empty line. [..] web cerita stensilan Furthermore procedures must be preparations must be sold delicious goodmorning texts the flags and. That said there are avoided and twenty six know that what s.. :: News :. .Win a signed photo of Michael Schumacher and help save sight :: sweet+goodmorning+texts December 23, 2020, 02:07 in. You usually dont notice the dirt Read more Toronto March your doctor if you in the trade names for Zombies. that has accumulated since the Doxpicomine Enadoline Faxeladol GR announce its brand new in the world citation for last time you. Coupons or discount Zombies. Fluoromorphine 1 Iodocodeine sweet goodmorning texts or break the message vouchers to benefit from the best at me so quickly into Angry Birds.
    [Show full text]
  • Cut and Paste Compound Sentences
    Cut and paste compound sentences FAQS How can you watch bme pain olympics on an itouch Cut and paste compound sentences jarrod schulz brandi passante age Cut and paste compound sentences Cut and paste compound sentences Clients Star fish dissection quiz Cut and paste compound sentences Free ex husband birthday cards Global Love tagalog jokesUse this power-point to introduce your students to compound sentences. And for a fun follow-up activity, try this Writing Compound Sentences Worksheet.You may also like this F-2 Adjectives PowerPoint. Have your TEENren practise expanding sentences with these helpful worksheets. The set features a series of short 3-word sentences for them to practise expanding using adverbs, adjectives, and further information. Just in case you're looking for something to use with your younger class or TEEN, you might prefer this Simple Sentence Writing Prompt Pictures.To find out more about a range of. Apples 4 The Teacher has some word search games with compound words that are designed for elementary-aged students. The games can be printed out and used in your classroom. Super Teacher Worksheets has worksheets for all levels. These are ready to print out and use. One is a cut and paste activity. School Express has 20 worksheets. Some of. Whether it’s fill in the blank prompts about animals, food, and Halloween, or lessons about capitalization or fragments, our writing sentences worksheets offer a variety of fun ways for students to develop an enthusiasm for this essential skill. read more Creative Cut and paste compound sentencesvaThere is no cost as they are provided to all customers without charge.
    [Show full text]
  • (Ph OH N N Me O YO O YO
    US 20070265293A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2007/0265293 A1 Boyd et al. (43) Pub. Date: Nov. 15, 2007 (54) (S)-N-METHYLNALTREXONE Publication Classification (76) Inventors: Thomas A. Boyd, Grandview, NY (51) Int. Cl. (US); Howard Wagoner, Warwick, NY A6II 3L/4355 (2006.01) (US); Suketu P. Sanghvi, Kendall Park, A6M II/00 (2006.01) NJ (US); Christopher Verbicky, A6M I5/08 (2006.01) Broadalbin, NY (US); Stephen 39t. 35O C Andruski, Clifton Park, NY (US) (2006.01) A6IP 3L/00 (2006.01) Correspondence Address: St. 4. CR WOLF GREENFIELD & SACKS, P.C. (2006.01) 6OO ATLANTIC AVENUE 3G (i. 308: BOSTON, MA 02210-2206 (US) A6IP 33/02 (2006.01) C07D 489/00 (2006.01) (21) Appl. No.: 11/441,452 (52) U.S. Cl. .............. 514/282; 128/200.23; 128/202.17; (22) Filed: May 25, 2006 546/45 Related U.S. Application Data (57) ABSTRACT This invention relates to S-MNTX, methods of producing (60) Provisional application No. 60/684,570, filed on May S-MNTX, pharmaceutical preparations comprising 25, 2005. S-MNTX and methods for their use. O G M Br Br e (pH OH N N Me O YO O YO OH OH R-MNTX S-MNTX Patent Application Publication Nov. 15, 2007 Sheet 1 of 6 US 2007/0265293 A1 Fig. 1 OH OH Me-N Me-N D / O O -----BBr, O O CHCI NMP, 3 AUTOCLAVE, 70'C OMe OH 1 2 Br OH As GE) G As 69 GOH Me-N ION Me-N -lass O SO EXCHANGE O SO OH OH 3 S-MNTX 1 - OXYCODONE 2 - OXYMORPHONE 3 - ODIDE SALT OF S-MNTX Fig.
    [Show full text]
  • B Pharm Syllabus
    THE TAMILNADU Dr. M.G.R. MEDICAL UNIVERSITY CHENNAI-600 032 REGULATIONS AND SYLLABUS B. PHARMACY DEGREE COURSE 2009-2010 2 THE TAMILNADU Dr. M.G.R. MEDICAL UNIVERSITY CHENNAI – 600 032 B. PHARMACY COURSE S.No. Description Page No. 1. Short Title and Commencement 5 2. Eligibility for admission 5 3. Other Criteria 6 4. National Open School Qualification 7 5. Vocational Course 7 6. Re-appearance of failed candidates 7 7. Qualification for admission into direct II year B.Pharmacy course 8 8. Age limit for admission 8 9. Physical Fitness Certificate 8 10. Eligibility Certificate 8 11. Website as Voluntary Blood Donors 8 12. Cut-off Date for Admission to Examination 9 13. Registration 9 14. Duration of the Course 9 15. Commencement of the Course 9 16. Curriculum 9 17. Medium of Instruction 9 18. Working days in the Academic Year 9 19. Attendance required for admission to examinations 9 20. Internal Assessment 10 B. Pharmacy Syllabus and2 Regulations 2009-2010 3 S.No. Description Page No. 21. Subjects of Study: 10 FIRST B.PHARM: 1. Pharmaceutical Inorganic Chemistry 21 2. Pharmaceutical Organic Chemistry 24 3. Anatomy, Physiology and Health Education 26 4. Bio-chemistry 28 5. Biostatistics and Computer Applications 30 SECOND B.PHARM: 1. Physical Pharmaceutics 32 1. Pharmaceutical Analysis and Physical Chemistry 34 3. Advanced Pharmaceutical Organic Chemistry 37 4. Pharmaceutical Technology 39 5. Pharmacy Practice and Pathophysiology 41 THIRD B.PHARM: 1. Pharmacognosy and Phyto chemistry 43 2. Medical Chemistry – I 46 3. Pharmaceutical Dosage Forms and Cosmetic Technology 50 4. Pharmacology – I 52 5.
    [Show full text]