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Chiral Synthetic Drugs over the last 20 Years

Chiral Synthetic Drugs over the last 20 Years
Chiral Synthetic Drugs over the last 20 Years

Top Curr Chem(2007)269:273–299

DOI10.1007/128_2006_072

?Springer-Verlag Berlin Heidelberg2006

Published online:11November2006

From Racemates to Single Enantiomers–

Chiral Synthetic Drugs over the last20Years

Hisamichi Murakami

Ex-Director of R&D Division,Y amakawa Chemical Industry Co.,Ltd,Kitaibaraki,

319-1541Ibaraki,Japan

HsMurakami@https://www.doczj.com/doc/1d3907000.html,

1Introduction (274)

2New Drugs Launched in1985–2004and their Chirality (275)

3Origins of New Drugs:Countries and Companies (277)

4Therapeutic Aspects (278)

5Structural Features of Single Enantiomers (281)

5.1Number of Chiral Centers (281)

5.2Molecular Weights (283)

5.3Hydrogen Bond Donors and Acceptors (284)

6Manufacturing Methods:Introduction of Chirality (285)

6.1Single Enantiomers with One Chiral Center (286)

6.1.1Chirality Pool (286)

6.1.2Optical Resolution (286)

6.1.3Asymmetric Syntheses (288)

6.1.4Racemic Switches (289)

6.2Single Enantiomers with Two or More Chiral Centers (289)

6.2.1Synthesis from Chiral Building Blocks (290)

6.2.2Resolution of Racemates (290)

6.2.3Separation of Diastereomer Mixtures (291)

6.2.4Crystallization-induced Asymmetric Transformations (291)

6.2.5Diastereoselective Reactions (292)

7Examples of Excellent Syntheses (292)

7.1Indinavir Sulfate(Crixivan) (292)

7.2Aprepitant(Emend) (293)

7.3Tadala?l(Cialis) (294)

7.4Sertralin(Zoloft) (295)

8Conclusions (296)

References (298)

Abstract Before1985,most chiral drugs newly introduced annually to the market were racemates and only three to?ve drugs were launched yearly as single enantiomers.Since then,the situation has changed dramatically,with racemates being introduced only rarely

274H.Murakami to the market.In2004,all the new synthetic drugs(13in the world)were launched as single enantiomers.

This article summarizes the change of chiral drugs in the last two decades from race-mates to single enantiomers and outlines the structural features of these new drugs and the manufacturing technologies applied to introduce chirality to them–chirality pool, various types of resolutions and asymmetric syntheses,of which the new technologies developed recently are highlighted.

Keywords Asymmetric synthesis·Chirality pool·Resolution·Single enantiomer·Synthetic drug

Abbreviations

ACE Angiotensin converting enzyme

CMV Cytomegalovirus

CNS Central nervous system

CSA10-Camphorsulfonic acid

DBTA O,O -Dibenzoyl-tartaric acid

DTTA O,O -Ditoluoyl-tartaric acid

HMG-CoA3-Hydroxy-3-methylglutaryl coenzyme A

IPA Isopropyl alcohol

MA Mandelic acid

MBAα-Methylbenzylamine

Mw Molecular weight

NCE New chemical entitiy

NCS N-Chlorosuccinimide

NK1Neurokinin1

SMB Simulated moving bed

TA Tartaric acid

p-TSA p-Toluenesulfonic acid

1

Introduction

In1984,E.J.Ariens presented a paper,in which he declared the therapeuti-cally non-active isomer in a racemate should be regarded as an impurity(50% or more).He also pointed out that in clinical pharmacology,and particularly in pharmacokinetics,neglect of stereoselectivity in action leads to the per-formance of expensive“highly sophisticated scienti?c nonsense”[1].At that time,most of chiral synthetic drugs on the market were used as racemates and the proportion of single enantiomers was only12%of chiral drugs[2,3]. After two decades,most of newly launched chiral synthetic drugs are single enantiomers,and only one or two racemates or diastereomers are introduced in a year.For the?rst time in2004,all the approved chiral synthetic drugs went to market as single enantiomers.In this article,the course of these changes proceeded in these two decades,that is“from racemates to single

From Racemates to Single Enantiomers275 enantiomers”,will be con?rmed and the technologies supporting this revo-lution will be reviewed.

2

New Drugs Launched in1985–2004and their Chirality

In the20years between1985and2004,754new drugs(new chemical and biological entities)were launched in the world.These drugs were classi?ed according to their source and chirality,and the number of drugs appeared in each four-year period are illustrated in Table1.These data are mainly obtained from the chapters“To Market,to Market”of Annual Reports in Medicinal Chemistry,published annually under the sponsorship of the Divi-sion of Medicinal Chemistry of the American Chemical Society[4].

As shown in Table1,among the total754entities,synthetic drugs con-stitute the largest group of550(73%),followed by semisynthetics(128)and biologicals(76).The number of newly launched drugs decreases through this period constantly,from204in1985–1988to113in2001–2004.

With synthetic drugs,the proportion of achiral drugs decreased gradually from48%(1985–1988)to35%(2001–2004).The most striking observations are the increase of single enantiomers in chiral drugs and the decrease of racemates,which dominated two-thirds of chirals in1985–1988.Afterwards they gradually declined and then dramatically dropped to only3at the open-ing of the21st century.In the year2004,among the16newly approved Table1New drugs launched in1985–2004

Y ear1985–881989–921993–961997–002001–04Total Grand total204141160136113754 Synthetics total14610411610975550 Achiral7046494626237 Chiral total7658676349313 Racemates503230223137 Diastereomers250029 Single enantiomers(SE)2421374144167

SE a/Chiral(%)31.636.255.265.689.853.5 Achirals/Synthetics(%)47.944.242.241.834.743 Semisynthetics total4124282015128 Biologics total17131672376 Natural13711426 Recombinant461561950

a Single enantiomers

276H.Murakami synthetic drugs,13chirals were all single enantiomers and the rest,only three,were achiral.These changes to synthetic drugs with chirality are illus-trated in Fig.1.

The move from racemates to single enantiomers has been driven by the guidelines issued by regulatory authorities in the late1980s,which require the applicants of racemic drug candidates to submit scienti?c evidences to use racemates not as single enantiomers[5,6].As a consequence,pharmaceutical companies had to investigate the stereochemical features of their drug can-didates in the early stage of development and,in most cases,they selected single enantiomers for further development.Racemates were chosen only ex-ceptionally,when the single enantiomer racemizes easily in vitro and/or in vivo,individual enantiomers have similar pharmacological and toxicological pro?les,or the use of racemates results in some synergic effects to exhibit better pharmacological or toxicological outcome,etc.

The number of achiral drugs also decreased signi?cantly but the propor-tion of35–40%has been kept in synthetic drugs.Newer therapeutic groups, such as angiotensin II receptor antagonists,tyrosine kinase inhibitors all con-sist of achiral compounds.

The new launches of semisynthetic drugs have nearly halved in the last ten years,from84new entities in1985–1994to44in1995–2004.This decrease of new launches is mainly ascribed to the cease of development of cephalosporin antibiotics(from19new launches in the former ten years to only three in the latter).A slow-down of the appearance of steroids and macrolide antibiotics is also observed,from18and15to11and8.

Although the biological drugs including recombinant products were launched at a nearly constant pace to the total of76entities in these20years, natural products extracted from plants,animals or fermentation broths de-creased signi?cantly at the end of20th century.On the contrary,approved

Fig.1New launches of synthetic drugs:1985–2004

From Racemates to Single Enantiomers277 numbers of recombinant products,?rst launched at the end of1980s,is in-creasing constantly and in2004reached the total of50.

3

Origins of New Drugs:Countries and Companies

In Table2,the numbers of new synthetic drugs launched in each four-year period are listed according to their chirality and countries of origin.The largest number of chiral and single enantiomeric drugs have their origins in Table2Origins of chiral synthetic drugs:1985–2004

Originated in Type a1985–881989–921993–961997–002001–04Total USA Synth.3319263731146

Chiral221114192591

SE9711142566 Japan Synth.3529372017138

Chiral151825141183

SE75125938

UK Synth.11171313761

Chiral41065429

SE1245416 Switzerland Synth.69105535

Chiral4473220

SE2233111 France Synth.16275535

Chiral8143319

SE102238 Germany Synth.148913347

Chiral6438122

SE010607

Italy Synth.17443028

Chiral9212014

SE321107 Sweden Synth.3312211

Chiral221218

SE011114 Other countries Synth.1113911549

Chiral6667227

SE1134110 Total Synth.14610411610975550

Chiral7658676349313

SE2421374144167

a Synth.=synthetics,Chiral=racemates+diastereomers+single enantiomers(SE)

278H.Murakami the USA,followed by Japan and the UK.In these three countries,204chiral drugs(65.0%of total314)were discovered,of which121entities are single enantiomers(72.0%of total167).In Switzerland,France and Germany,a sig-ni?cant number of single enantiomers(26,15.5%)are also originated.Chiral synthetic drugs discovered in these six countries account for84.4%of chiral drugs(265entities)and87.5%of single enantiomers(147).

The change to single enantiomers proceeded most rapidly in the USA and the UK as early in the1993–1996period,when the proportion of single enan-tiomers in chiral drugs has reached to78%in the USA and67%in the UK. After1997,all the10new chiral drugs originated in the UK went to market as single enantiomers,and later in2001–2004,25new chiral drugs discovered in the USA were also launched entirely as single enantiomers.

As to the originators,Merck leads the discovery of single enantiomers with 10NCE’s in the past20years,followed by AstraZeneca(8),Hoffmann-La Roche(7),Novartis(7),and Glaxo SmithKline(6).P?zer itself discovered 4NCE’s in this period,but as a result of mergers with Warner-Lambert and Pharmacia,11NCE’s have their origins in the P?zer group.

4

Therapeutic Aspects

The aspects in the therapeutic areas are indicated in Table3,where single enantiomeric new drugs were actively developed.

1)Cardiovascular Agents:32NCE’s were launched in this area,of which an-

giotensin converting enzyme(ACE)inhibitors are ranked as the top of all therapeutic groups with15new drugs.The?rst ACE inhibitor,capto-pril,was introduced to the market in1981,followed by enalapril in1984, then15new entities of this type were launched from1987to the end of the20th century.Angiotensin II receptor antagonists,recently developed potent and selective antihypertensives led by losartan(1994),are all achi-ral compounds except for valsartan(1996),which is an optically active L-valine derivative,and candesartan silexetil(1997),a racemic prodrug.

The second active area of the cardiovascular agents is antihyperlipopro-teinemic agents with?ve synthetic HMG-CoA reductase inhibitors (statins)and a new type of small molecule cholesterol absorption inhibitor (ezetimibe,2002).Lovastatin and two other statins introduced in1980’s are semisynthetic compounds derived from fermentation products and not counted in Table3.Six antithrombotics have been introduced to the market in this period,including entities with various chemical structures from prostaglandin to oligopeptides.

2)The second largest therapeutic group is antivirals,including anti-HIV

agents.Seven reverse transcriptase inhibitors and eight protease inhibitors

From Racemates to Single Enantiomers279 Table3Single enantiomers by therapeutic categories

Therapeutic categories1985–881989–921993–961997–002001–04Total Cardiovascular agents

Antihypertensives4762120 ACE inhibitors(4)(5)(5)(1)(0)(15) Others(0)(2)(1)(1)(1)(5) Antihyperlipoproteinemics00123a6 Antithrombotics100416 Antivirals

HIV reverse transcriptase0122b27 inhibitors

HIVprotease inhibitors003328 Others002013 Antineoplastics

Antimetabolites1141310 Pt complexes001102 Peptides and others10203c6 Antibacterials

Antibiotics(carbapenem,etc.)3d2e21210 (two adjuvants included)

Quinolones and others0012f14 Antiglaucomas003126 Antidepressants020035 Hormonals(peptides,etc.)001304 Antidiabetics000213 Antiemetics00102g3 Antimigraines000123 Total1013292529106 Grand total h2421374144167

a ezetimibe

b efavirenz

c bortezomib

d cilastatin

e tazobactam

f linezolid

g aprepitant

h of all single enantiomers in all therapeutic categories

were introduced to the market to overcome HIV infections.As to reverse transcriptase inhibitors,semisynthetic products,zidovudine(1987)and di-danosine(1991)were launched at?rst,then six nucleosides,e.g.,zalcitabine (1992)and stavudine(1994)followed.To manufacture these compounds, several processes have been developed and some of them are derived from natural or fermented nucleosides,such as adenosine,guanosine or uridine.

280H.Murakami Other than nucleosides,efavirenz was introduced to the market in1998as

a unique non-nucleoside HIV reverse transcriptase inhibitor.

The?rst HIV protease inhibitor,saquinavir,was launched in1995,fol-lowed by seven related compounds and used in combination with reverse transcriptase inhibitors.These are peptidomimetic compounds and have relatively complex structures with large molecular weights and many chi-ral centers.

Apart from anti-HIV drugs,three antiviral compounds for herpes,and AIDS-related CMV infections have been introduced.Two antiviral com-pounds for in?uenza,launched in1999,were not included in this sur-vey,because these are semisynthetic compounds derived from natural resources.

3)Antineoplastics,with18new entities,constitute the third group,of which

ten antimetabolites,two platinum complexes,four hormonal peptides and two others were launched.As antimetabolites,two antifolates,raltitrexed (1996)and pemetrexed(2004),have been introduced,besides eight nucle-osides.Bortezomib(2003)is the?rst proteasome inhibitor for the treat-ment of multiple myeloma,and chemically,it is the?rst boronic acid derivative as a pharmaceutical.Amrubicin(2002)is also the?rst com-pletely synthetic anthracycline antibiotic.

4)In the?eld of antibacterials,eightβ-lactam antibiotics,twoβ-lactamase

inhibitors as the adjuvants toβ-lactam antibiotics,three quinolone deriva-tives and a new class of antibacterial agent,linezolid(2000),have entered to market.Imipenem was launched in1985as the?rst carbapenem antibi-otic,followed by panipenem(1994)and three1β-methyl-carbapenems, meropenem(1994),biapenem and ertapenem(2002).

5)Six antiglaucomas were launched in these20years,of which two carbonic

anhydrase inhibitors,dorzolamide(1995)and brinzolamide(1998),have appeared in addition to four prostaglandins,represented by unoprostone (1994).

6)Five antidepressants were introduced to the market,of which sertralin

(1990)and paroxetine(1991)are now blockbusters.Escitalopram(2002) is a racemic switch,and atomoxetine(2003)the?rst non-stimulant drug for attention de?cit hyperactivity disorder(ADHD).Duloxetine(2004) is approved for the treatment of stress urinary incontinence and dia-betic peripheral neuropathic pain,in addition to the treatment of major depression.

7)In the?elds of antiemetics and antimigraines,achiral or racemic com-

pounds have been used initially,but single enantiomers were recently introduced to the market;ramosetron(1996),palonosetron(2003)and aprepitant(2003)as antiemetics,zolmitriptan(1997),eletriptan(2001) and frovatriptan(2002)as antimigraines.Among them,aprepitant is the ?rst NK1receptor antagonist,while the other antiemetics are5HT3recep-tor antagonists.

From Racemates to Single Enantiomers281 5

Structural Features of Single Enantiomers

A number of large and complicated molecules are observed in recent new drugs especially in single enantiomeric synthetics.Number of chiral cen-ters,molecular weights and number of hydrogen bond donors in the drug molecules were selected as the measures of structural complexity and their change in the recent twenty years were surveyed.

5.1

Number of Chiral Centers

Table4shows the numbers of single enantiomers and racemates by the num-ber of chiral centers and the launched years.

1)The numbers of chiral centers of single enantiomers distribute from one to

over ten,but the entities with one or two chiral centers account for more than half of all the single enantiomers.Among17entities with seven or more chiral centers,14are peptides consisting of7to38amino acid units, two are oligonucleotides(fomvirsen(1998)and pegaptanib(2004)),and one polymeric Zn complex of amino acid derivative(polaprezinc(1994)).

2)The number of single enantiomers having one chiral center increased sig-

ni?cantly after1995.While only14entities with one chiral center were launched in ten years from1985to1994,44have entered the market in the period from1995to2004.On the other hand,launches of racemates Table4New chiral synthetic drugs:The number of chiral centers

No.of Launched in

Chiral1985–881989–921993–961997–002001–04Total Ratio(%)

centers

Single1641121165834.7 Enan-24956113520.9 tiomers3556332213.2 4216451810.8

5–6415251710.2

≥7314541710.2

Total2421374144167100.0

Racem-144282714311684.7

ates253140139.5≥3112408 5.8

Total503230223137100.0

282H.Murakami with one chiral center had dramatically decreased from89in1985–1994 to27in1995–2004,clearly re?ecting the switch from racemates to single enantiomers.

3)Single enantiomers with two chiral centers had also increased moderately

from15in1985–1994to20in1995–2004.

4)Fifty-seven new single enantiomeric drugs having three to six chiral cen-

ters were launched in the past20years,of which26appeared in1985to 1994,and31in1995to2004.The largest group in this category is ACE in-hibitors with13entities,of which ten were launched in the?rst ten years.

Tied for second with eight each are the antineoplastics with nucleoside moieties and HIV protease inhibitors;the latter were all introduced after 1995.Seven each ofβ-lactam antibiotics and prostaglandins,of which four entities are antiglaucomas,have also entered the market.These?ve groups of new drugs constitute about three quarters of the total57new entries (Table5).

5)Contrary to single enantiomers,most of the racemates(116of total137)

have only one chiral center and the racemates with two chiral centers are merely13,of which most compounds are the mixture of two antipodes with the same relative con?guration such as(R?,R?)or(R?,S?).Only three compounds are the mixture of four isomers and the two of them(lox-oprofen(1986)and troglitazone(1997))have labile chiral centers easily converting in the body.Introduced in1985to1997,?ve racemates with three or four chiral centers,all consist of two enantiomers.

As the increasing number of isomers causes a sharp decrease in the pro-portion of the active isomers,inventors should inevitably select structures with the de?nite relative con?guration devising any stereoselective synthetic schemes to reduce the number of isomers.

Table5Major drug groups:The number of chiral centers(1985–2004)

Number of chiral centers123456>=7Total ACE inhibitors02a10b030015

HIV protease inhibitors00233008 Nucleosides

Antineoplastics00260008 Antivirals25000007

β-Lactam antibiotics01230208 Prostaglandins00016007c Peptides0000201315

a Besides these,captopril was launched in1981

b Besides these,appeared enalapril(1984),and fosinopril(1991,diastereomer)

c Besides these,four diastereomers an

d on

e racemate have been launched

From Racemates to Single Enantiomers283 5.2

Molecular Weights

As a measure of the size of drug molecules,molecular weights(Mws)of new drugs were surveyed and listed in Table6.In case a drug is sold as its salt,the molecular weight of the free form is usually adopted.The average Mws of the entities launched in each four-year period were calculated,excluding the ones with larger Mws than800,which are peptides or oligonucleotides.

1)As shown in Table6,the Mws of most single enantiomers reside in the

range of200and500(76%),and only17large molecules with Mws500–800(10%)are used,except for17peptides and2oligonucleotides(Mw> 800).The average Mws in1985–1992(about340)have increased sharply to 408in1993–1996and the level of370is kept thereafter.This is explained by the increase in the large molecules with Mws over500after1995,rep-resented by HIV protease inhibitors.

2)Of the17drugs with Mws500–800,12are administered orally.Be-

sides eight HIV protease inhibitors with Mws505.6–721.0,tenofovir diso-proxil fumarate(antineoplastic,519.4),aprepitant(antiemetic,534.4), atorvastatin(antihyperlipoproteinemic,558.6)and montelukast(antialler-gic,586.2)are sold as tablets or capsules.

3)In comparisons with single enantiomers,achiral drugs are smaller and

racemates are about the same in their Mws.Particularly to be commented, Table6Molecular weights of synthetic drugs

Molecular Launched in

Weight1985–881989–921993–961997–002001–04Total Single<200000134 Enantiomers200–300107811844 300–40056881441

400–500571110942

500–6000014510

600–800104117

>8003156419

Total2421374144167

Average Mw a341.5336.6408.2373.7373.5367.0 Racemates Number of drugs503230223137 Average Mw a349.7359.6377.0373.8437.0364.3 Achirals Number of drugs7046494626237 Average Mw a318.4314.6328.5339.8389.5331.4

a Entities with Mws>800are excluded

284H.Murakami the average Mws of these two categories are constantly increasing year to year.

4)As a whole,the average size of drug molecules has gone up in the last

20years:the ratio of average Mws of(2001–2004)/(1985–1992)for single enantiomers is1.09,for racemates1.25and1.22for achirals.In2001–2004, the average Mws of single enantiomers is smaller than those of the other groups.

5.3

Hydrogen Bond Donors and Acceptors

C.A.Lipinski de?ned the number of OH and NH groups in a drug molecule as“hydrogen bond donors”and the number of oxygen and nitrogen atoms as “hydrogen bond acceptors”,recognizing them as measures of drug permea-bility and absorption in the body,along with Mws and log P’s(P:partition coef?cient of a drug compound in1-octanol-water).He proposed the“rule of 5”upon the investigation of a large number of marketed and investigational drugs[7].The rule predicts a poor absorption or permeation in the body for

a drug compound,which meets one or two of the four criteria shown below:

1)There are more than5hydrogen bond donors.

2)The molecular weight is over500.

3)The log P is over5.

4)There are more than10hydrogen bond acceptors.

Here the numbers of hydrogen bond donors of the new synthetic drugs launched after1985are listed in Table7.

As shown in Table7,about90%of single enantiomers have1to5hydro-gen bond donors,and only6chemical entities(4.0%)have6or7donors. Among these six drugs,only droxidopa(Mw213.2)and saquinavir(670.8)are administered orally and other four(Mw285–483)by injection.

The average numbers of hydrogen bond donors calculated for the entities having less than10donors are as follows:single enantiomers2.37,racemates 1.41and achirals1.80.The implication of these differences in the number of hydrogen bond donors is not certain.

As to the single enantiomers and racemates,their average numbers of chi-ral centers are2.43and1.20,respectively,and closely resemble the number of hydrogen bond donors.But the numbers of hydrogen bond donors scatter in wide range from zero to over?ve for all single enantiomeric and racemic drugs with one to?ve chiral centers.No apparent correlations are observed between these two numbers.

Hydrogen bond acceptors are also checked and12single enantiomers are found to have11to15acceptors,excluding peptides and oligonucleotides.Of these12drugs,seven have large Mws over500,of which four are HIV protease inhibitors and administered orally.Among racemates and achiral drugs,enti-

From Racemates to Single Enantiomers285 Table7Hydrogen bond donors:Synthetic drugs1985–2004

Launched in

H-bond donors1985–881989–921993–961997–002001–04Total

Single0001247

Enan-157510936 tiomers277109538 34266826

41177723

52121511

6–9121026

≥10(4)(1)(5)(6)(4)(20)

Total20+(4)20+(1)32+(5)35+(6)40+(4)147+(20)

Average a 2.58 2.40 2.71 2.19 2.72 2.37 Racem-No.of503229+(1)20+(2)3134+(3) ates drugs 1.60 1.34 1.21 1.52 2.33 1.41 Average a

Achirals No.of704648+(1)4626236+(1) drugs 1.90 1.65 2.02 1.76 1.85 1.80

Average a

a Drugs with more than10hydrogen bond donors were omitted for calculation of the average

ties having more than ten hydrogen bond acceptors are rarer than in single enantiomeric drugs(only three in racemates and?ve in achirals).

6

Manufacturing Methods:Introduction of Chirality

How to introduce the chirality to the target drug molecule is the inevitable subject in the syntheses of single enantiomeric drugs and innumerable pro-cedures have been developed and applied in the pharmaceutical industry.

Single enantiomeric drugs launched between1985and2004belong to di-verse structure types and have one to more than ten chiral centers.Here,for convenience’s sake,these drugs were divided into the entities having only one chiral center and those with two or more chiral centers,to inspect and classify the methods of introducing the chirality.

Usually,several processes are developed to manufacture a single target drug molecule,and it is not certain which process is actually adopted in commercial production.Moreover,process changes are often reported even after the launch of new drugs.The manufacturing processes referred to the individual drug compounds in this chapter are estimated according to the author’s best knowledge.

286H.Murakami 6.1

Single Enantiomers with One Chiral Center

As shown in Table4,58entities with one chiral center were launched in1985–

2004.Their manufacturing methods are classi?ed conventionally,as follows: 1)Chirality pool:syntheses from optically active intermediates or building

blocks

2)Optical resolution of the appropriate racemates,in the course of any stage

in the manufacturing processes

3)Asymmetric synthesis,including enzymatic or biological procedures. Chirality pool originally meant the relatively inexpensive natural or fer-mented products,such as carbohydrates,amino acids,oxy-acids,alkaloids,

terpenes,etc.Recently,a variety of optically active compounds are produced on a large scale by various methods and available easily from a number of

suppliers.Therefore it is relevant to include these products as important con-stituents of chirality pool.

The chirality of single enantiomeric drugs with one chiral center launched

in1985–2004are introduced by the three procedures,according to the au-thor’s estimation or supposition,as follows:

Chirality pool:26

Optical resolution:27

Asymmetric synthesis:5

6.1.1

Chirality Pool

Nearly a half of single enantiomeric drugs with one chiral center are produced

by introducing their chirality,using optically active compounds or chirality

pool as the starting material or intermediates and combining with achiral compounds at an appropriate stage of the synthetic sequence.

Natural amino acids are the most frequently used chirality pool(of 14drugs),followed by unnatural amino acids and amino acid analogs(6),op-

tically active glycidol derivatives(6).Most frequently used amino acids are L-Cys(bucillamine(1987),telmesteine(1992)and fudosteine(2001)),L-Glu (raltitrexed(1996),carglumic acid(2003)and pemetrexed(2004))and L-Val

(valaciclovir(1995)and valsartan(1996)).

6.1.2

Optical Resolution

Resolution is the most frequently utilized technology to produce single enan-

tiomeric new drugs.As shown in Table8,27new single enantiomeric drugs

launched in1985–2004are estimated to be manufactured by using any kind

From Racemates to Single Enantiomers287 Table8Optical resolution:Single enantiomers with one chiral center

Drug Name(Launched in)Resolving Agents Substrates

Resolution of starting materials

Flunoxaprofen(1987)L-ephedrine4-(α-cyanoethyl)phenol Dexrazoxane(1992)a not disclosed1,2-diaminopropane Tamsulosin(1993)(R)-MBA b substd.phenylacetone Tiagabine(1996)L-TA Et3-piperidinecarboxylate Clopidogrel(1998)L-TA2-Cl-phenylglycine Me ester Repaglinide(1998)N-Ac-L-TA1-Ar-isopentylamine Ramatroban(2000)(S)-MBA b3-oxo-tetrahydrocarbazole Levocetirizine(2001)L-TA4-Cl-benzhydrylamine Cinacalcet(2004)not disclosed1-α-naphthylethylamine Resolution of intermediates

Ropivacaine(1996)L-DBTA pipecolic anilide Pramipexole(1997)L-TA2-aminothiazole deriv. Rivastigmine(1997)L-DTTA N,N-diMe-MBA deriv. Bepotastine(2000)N-Ac-L-Phe4-diarylmethoxy-piperidine Levosimendan(2000)L-TA4-Me-pyridazinone deriv. Escitalopram(2002)c L-TA dimethylaminobutanol deriv. Duloxetine(2004)(S)-MA thiophene deriv.

Mitiglinide(2004)d(R)-MBA2-benzylsuccinic acid Resolution at the?nal step

Denopamine(1988)D-Ac-Phe racemate

Dexibuprofen(1994)a(S)-Me-Ph-butylamine racemate(ibuprofen) Ramostron(1996)D-DBTA racemate

Dexfen?uramine(1997)a(+)-camphoric acid racemate(fen?uramine) Levalbuterol(1999)a,d D-DTTA penultimate intermediate Dexmedetomidine(2000)a L-TA racemate(medetomidine) Frovatriptan(2002)(+)-CSA racemate

Atomoxetine(2003)d(S)-MA racemate

Eszopiclone(2004)a,e D-DBTA racemate(zopiclone) Pregabalin(2004)d,e(S)-MA racemate

a Racemic switch

b Reductive amination with a prochiral ketone

c Process change to SMB separation is reported

d Asymmetric synthesis developed as th

e alternative process

e Enzymatic kinetic resolutions are developed

of resolution,of which the majority of drugs are produced via diastereomer crystallization using resolving agents,except for one by continuous chro-matographic(SMB)resolution(escitalopram,2002)[8].

Diastereomer crystallization is well known as a classical resolution and apt to be thought of as out-of-date technology,but as a sharp increase of sin-

288H.Murakami gle enantiomeric drugs with one chiral center after1995,the number of new drugs manufactured by using this technology also increased dramatically: from only5entities in1985–1994to22in1995–2004.

Most frequently used resolving agents are natural L-tartaric acid and its bis-aroylated derivatives(D-or L-dibenzoyl-and ditoluoyl-),followed by(R)-or(S)-mandelic acid.

Basic resolving agents,represented byα-methylbenzylamine are used in ?ve resolutions.In the two cases,the amine is condensed with prochiral ke-tones and reduced to diastereomeric secondary amine mixtures,followed by separation by crystallization and hydrogenolysis,to give optically active pri-mary amines(tamsulosin(1993)and ramatroban(2000)).Benzylsuccinic acid is ef?ciently resolved by the salt formation with(R)-α-methylbenzylamine for the production of mitiglinide(2004).Alternative preparation via asymmetic synthesis is also developed for this entity.

Eszopiclone(2004),the racemic switch of a hypnotic,zopiclone,can be manufactured by classical resolution of the racemate or by enzymatic reso-lution of precursors[9].For pregabalin(2004),a classical resolution process using(S)-mandelic acid as the resolving agent was established at a rela-tively early stage of its development[10],but a more ef?cient manufacturing process by asymmetric synthesis[11]or enzymatic procedure is reportedly implemented in the commercial production.The newer processes by asym-metric reduction of precursor ketones are also developed for levalbuterol (1999)and atomoxetine(2003)(see next section).

In general,resolutions at an early step of the synthesis are recommended as the golden rule from the economical and environmental points of view.Ac-tually in this survey,only7resolutions are carried out at the starting step, 11at the intermediate steps,and9at the?nal step.Four of the nine resolved at the last stage are so-called racemic switches of generic drugs,and it may be reasonable to resolve the relatively cheap racemates(Sect.6.1.4).

6.1.3

Asymmetric Syntheses

Five new chemical entities are manufactured by using asymmetric synthe-ses.Early in1993,the commercial production of(S)-1,2-propanediol,the key intermediate of levo?oxacin,was commenced by a catalytic asymmetric hy-drogenation of hydroxyacetone.An asymmetric alkylation process was?rst applied in the production of efavirenz(1998),a unique non-nucleoside HIV reverse transcriptase inhibitor.The key step,addition of cyclopropylacetylene to a prochiral ketone in the presence of chiral aminoalchohol and BuLi,is achieved with an excellent enantioselectivity of98%[12].

For the stereoselective oxidation of the thioether group of omeprazole precursor to its(S)-sulfoxide,esomeprazole(2000),two processes,Sharpless oxidation using a Ti tartrate catalyst and a microbial oxidation,have been

From Racemates to Single Enantiomers289 developed,of which the former is estimated to be implemented in the com-mercial production[13,14].

Asymmetric reduction of the keto group with chiral borane reagents is uti-lized in the manufacture of brinzolamide and montelukast(both in1998). This procedure is also reported to be adopted in the improved syntheses of levalbuterol(1999)[15]and atomoxetine(2003)[16]instead of classical reso-lutions.

6.1.4

Racemic Switches

From the mid-1980s,the single enantiomeric version of racemic drugs in the market have been intensively developed as“racemic switches”,with the expectation that they would have a higher ef?cacy,better pharmacokinetic pro?les or reduced side effects and so on,in comparisons with the par-ent racemates.Some of them have been launched and,today,13racemic switches are identi?ed on the market,of which AstraZeneca’s antiulcerative esomeprazole is the most successful one[13].All these drugs have one chi-ral center with the exception of dexmethylphenidate,which has two chiral centers.

These switched single enantiomers are manufactured by any of the methods depicted in this chapter.Seven drugs are produced by using classi-cal resolution,of which,four are resolved at the?nal step of the syntheses as referred in Sect.6.1.2.Dexmethylphenidate(2002)is also probably made by the resolution of its threo-racemate,methylphenidate.Asymmeric syntheses are applied to the commercial syntheses of levo?oxacin(1993),levalbuterol (1999)and esomeprazole(2000).A new technology of SMB chromatographic separation is reportedly utilized in the production of escitalopram(2002). Levobupivacaine(2000)is produced by using Cbz-L-Lys as the starting mate-rial.As to the latest switch,eszopiclone(2004),several methods are developed for its manufacture,including classical resolution or chromatographic sepa-ration of the racemate and enzymatic kinetic resolution of the intermediate ester by using an immobilized lipase.

6.2

Single Enantiomers with Two or More Chiral Centers

Over100new drugs with more than one chiral centers were launched in these20years.But,as shown in Tables4and5,the entities with seven or more chiral centers are almost peptides,and the majority of drugs with four to six chiral centers belong to speci?c drug groups with their characteris-tic structures and synthetic methodologies,exempli?ed by prostaglandins or β-lactam antibiotics,etc.In this section,syntheses of single enantiomers hav-ing two or three chiral centers are scrutinized and the characteristic method-

290H.Murakami ologies different from those for the entities with only one chiral center will be highlighted.

There are?ve fundamental methods to construct single enantiomers hav-ing two or more chiral centers.

1)Synthesis from chiral building blocks

2)Resolution of racemates having de?nite relative con?gurations

3)Separation of the diastereomer mixture derived from a single enan-

tiomeric precursor

4)Crystallization-induced asymmetric transformation

5)Diastereoselective reaction

These methods will be outlined with some typical examples.

6.2.1

Synthesis from Chiral Building Blocks

Two or more optically active building blocks including chirality pool are com-bined successively.By repeating this procedure,large compounds having mul-tiple chiral centers such as peptides or oligonucleotides can be constructed. ACE inhibitors are,in principle,produced by this method,but in many cases, stereoselective reactions are introduced to reduce the number of necessary chiral intermediates(Sect.6.2.3).

As simpler examples,pidotimod(1993,immunostimulant)is synthe-sized by condensing L-pyroglutamic acid with(R)-thiazolidine-4-carboxylate; taltirelin(2000,CNS stimulant)by condensing L-His with L-ProNH2,and then with L-dihydroorotic acid derivative.

6.2.2

Resolution of Racemates

The racemic compounds having two or three chiral centers and the de?nite relative con?gurations such as(R?,R?)and(R?,S?)or cis and trans can be synthesized by stereoselective reactions and resolved to single enantiomers by a classical resolution using appropriate resolving agents(Table9).Sertralin (1990,antidepressant)and voriconazole(2002,antifungal)are the typical examples.Their racemates with cis-or trans-con?gurations are resolved to single enantiomers at the?nal step of the syntheses.But,regarding sertralin, the commercial process was recently reformed to an extremely rationalized scheme,starting the synthesis with continuous chromatographic resolution of the racemic starting material,a tetralone derivative,to its single enan-tiomers(see Sect.7.4)[17].

From Racemates to Single Enantiomers291 Table9Optical resolution:Single enantiomers with two chiral centers

Drug name(Launched in)Resolving agents Substrates

Resolution of starting materials

or Intermediates

Paroxetine(1991)L-TA penultimate intermediate

Moxi?oxacin(1999)L-and D-TA N-Bn-diazabicyclononane Emtricitabine(2003)enzyme penultimate intermediate Resolution of racemates

Sertraline(1990)a(R)-MA cis-racemate

Barnidipine(1992)L-malic acid diastereomers Dexmethylphenidate(2002)b BNDHP c threo-racemate

Voriconazole(2002)(R)-(+)-CSA(R?,S?)-racemate

a The process change to SMB completed

b Racemi

c switch

c(R)-(–)-binaphthyl-2,2 -diyl hydrogen phosphate

6.2.3

Separation of Diastereomer Mixtures

Starting with chiral building blocks,condensation reactions with appropriate prochiral compounds generate the second chiral centers in the products to af-ford diastereomer mixtures.Separation of the diastereomers can be achieved by the physical methods as crystallization or chromatography.In many cases, condensation reactions proceed in some diastereoselective fashion to give one isomer in more or less larger proportions.

For example,enalapril maleate(1984)is synthesized by condensing a dipeptide,L-Ala-L-Pro with4-phenyl-2-oxobutanoate and the resulted imine is hydrogenated over Pd catalyst to give a87:13mixture of(S,S,S)-and (R,S,S)-isomers,which is crystallized as the maleate salt to give the pure (S,S,S)-maleate.Most of ACE inhibitors are produced by using the similar procedures[18].

Palonosetron(2003,antiemetic)is synthesized by utilizing a chiral build-ing block,(S)-3-aminoquinuclidine,and an intermediate having a C=C dou-ble bond is hydrogenated over Pd catalyst to give a7:3diastereomer mixture, which is separated by one crystallization as hydrochloride to afford the pure (S,S)-isomer[19].

6.2.4

Crystallization-induced Asymmetric Transformations

When the second chiral center,generated as described above,is apt to iso-merize under mild conditions and the desired diastereomer crystallizes more

292H.Murakami easily than the undesired isomer,the desired isomer may be obtained in a nearly quantitative yield by adjusting the reaction conditions.This technol-ogy is utilized in the manufacturing processes of two new pharmaceuticals, aprepitant and tadala?l,both launched in2003(Sect.7).

6.2.5

Diastereoselective Reactions

By utilizing the preexisting chiral center as an intramolecular chiral aux-iliary,in some favorable cases,the second chiral center may be generated in a very high stereoselectivity.Typical examples of this category are found in the syntheses of indinavir(1996,diastereoselective alkylation and epoxi-dation),aprepitant(2003,hydrogenation over Pd catalyst),and rosuvastatin (2003,chelation-controlled borane reduction of1,3-hydroxyketone).

7

Examples of Excellent Syntheses

In this chapter,the recently developed manufacturing processes of four com-plicated single enantiomeric drugs,having two to?ve chiral centers,are presented to illustrate how various technologies are combined to elaborate simpli?ed and rationalized processes.

7.1

Indinavir Sulfate(Crixivan)

This is an HIV protease inhibitor having?ve chiral centers,launched by Merck in1996.The commercialized process starts with(1S,2R)-1-amino-2-indanol(1),which is prepared by a classical resolution of the racemate or by an asymmetric epoxidation of indene followed by Ritter reaction.1is acy-lated with phenylpropionyl chloride and derived to the acetonide2,which is treated with allyl bromide to give(S)-3in97:3stereoselectivity and95% yield.Without puri?cation,3is reacted with NCS in the presence of NaI in a two phase mixture of isopropyl acetate and aqueous sodium bicarbon-ate,followed by the treatment of obtained iodohydrin with a base to give the epoxide4in a quantitative yield(diastreomer ratio97:3).After one re-cystallization,puri?ed4is condensed with(S)-5and the protective group on the piperazine ring is replaced to give indinavir,which is puri?ed as sulfate[20–22](Scheme1).

The two of?ve chiral centers in the drug molecule are effectively gener-ated in two successive highly ef?cient diastereoselective reactions.The other three chiral centers come from1and5;the latter is also supplied through a resolution by diastereomer salt formation of the racemate.

九年级课文翻译完整版

九年级课文翻译 Document serial number【NL89WT-NY98YT-NC8CB-NNUUT-NUT108】

人教版初中英语九年级U n i t3课文翻译 SectionA2d 何伟:这是欢乐时光公园——我所在城市最大的游乐园! 艾丽斯:要尝试一些乘骑项目,我好兴奋呀! 何伟:我们应该从哪里开始玩呢?有太空世界、水上世界、动物世界…… 艾丽斯:哦,你能先告诉我哪儿有洗手间吗? 何伟:什么休息室你想要休息吗但是我们还没有开始玩呢! 艾丽斯:哦,不是,我的意思不是休息间。我的意思是……你知道的,卫生间或盥洗室。何伟:嗯……那么你是指……厕所? 艾丽斯:正是!对不起,也许“洗手间”一词在中国不常用。 何伟:对,我们通常说“厕所”或“卫生间”。就在那边。 艾丽斯:好的,我会很快的!我想知道公园今天何时关门。 何伟:九点三十,你不必着急! SectionA3a 欢乐时光公园——永远快乐的时光 [艾丽斯和何伟在太空世界。] 艾丽斯:我想知道我们接下来应该去哪里? 何伟:那边那个新项目怎么样? 艾丽斯:好吧……看起来蛮吓人的。 何伟:快来吧!我保证它将激动人心!如果你害怕,只要大叫或者抓住我的手。 [云霄飞车之后……] 艾丽斯:你是对的!太有趣了!起初我好害怕,但大声喊叫还蛮管用的。 何伟:瞧,那玩意并不糟糕,对吧?某些东西你不去尝试,就绝不会知道。 艾丽斯:对,我很高兴我试过了! 何伟:你现在想去水上世界么? 艾丽斯:好,但我很饿。你知道我们在哪里能吃到好的快餐? 何伟:当然!我建议在水上世界的水城餐馆,那里有美味可口的食物。 艾丽斯:好极了!我们走! [在前往水城餐馆途中,艾丽斯和何伟经过鲍勃叔叔餐馆。] 艾丽斯:看!这家餐馆看起来蛮有趣的。这招牌上说这儿每晚有摇滚乐队演出。

外研版高中英语选修七重点短语

外研版高中英语选修七重点短语 Module 1 1. defend sb./sth. from... 保护某人免遭……defend sb./sth. against…保护某人抵御…… 2. of value=valuable 有价值的,有用的value sth at+价钱, 给……估价为……value sth 重视 3. on(an/the) average 平均起来above / below the average 在一般水平以上/以下 4. deserve sth /to do 应得/理应…… deserve to be done=deserve doing 值得被,应该 5. at one point 曾经,一度on the point of doing sth. 正要做某事之时 off the point 离题,偏题to the point 中肯,扼要 There is no point in doing sth. 做某事没有用,没必要 6. There is no doubt that... 对……没有疑问There is no doubt about sth. 对某事没有疑问 There is much doubt whether... 有人怀疑…… I don't doubt that... 我不怀疑…… I doubt whether / if... 我怀疑…… without / beyond doubt 毫无疑问 7. rely on/upon...= depend on/upon... 依赖,依靠…… rely on sb. to do sth.= rely on sb. / one’s doing sth. 指望某人干某事 rely on sb. for sth. 指望某人某事rely on it that... 相信…… 8. for an instant 片刻,一瞬间in an instant 立即,马上 the instant... 一……就…… = the moment = the minute = as soon as 9. appoint sb.(to be)/(as)... 任命某人为…… appoint sb. to do sth. 委任某人做某事 appoint some time / some place for sth. 为某事确定某时间/ 地点 make/fix an appointment with sb. 与某人约会keep / break an appointment 守约/失约 https://www.doczj.com/doc/1d3907000.html,mit suicide 自杀commit a mistake 犯错commit sth. to sb. 把某物托付给某人 11. apologise to sb. for sth. 因某事向某人道歉 make an apology to sb. for sth. 因某事向某人道歉 accept/refuse an apology 接受/拒绝道歉 12. take possession of 占有,占据,拥有 in possession of 拥有,占有in the possession of 被……占有/控制 come into possession of 占有…… come into one's possession 被某人占有 13. be based on/upon 根据,以……为基础 14. if so 如果这样的话if any 假如有的话 if not 如果不是这样if possible 如果可能的话 15. grow up 长大 16. rescue …from… 把…某种状况下解救出来 17. set (up) a record 创记录 18. name sb. after … 用……给某人命名 Module 2 1.settle down 坐下;定居;(使)安静下来 settle down to sth. 开始认真对待;定下心来做 settle sth. with sb. 与某人解决某事 2.elect sb.+ (as) n./ 职位推选某人为…… 3.be suitable for... 适合…… 4.attract/draw one's attention 吸引某人的注意力

四种翻译方法,十种翻译技巧

四种翻译方法 1.直译和意译 所谓直译,就是在译文语言条件许可时,在译文中既保持原文的内容,又保持原文的形式——特别指保持原文的比喻、形象和民族、地方色彩等。 每一个民族语言都有它自己的词汇、句法结构和表达方法。当原文的思想内容与译文的表达形式有矛盾不宜采用直译法处理时,就应采用意译法。意译要求译文能正确表达原文的内容,但可以不拘泥与原文的形式。(张培基) 应当指出,在再能确切的表达原作思想内容和不违背译文语言规范的条件下,直译有其可取之处,一方面有助于保存原著的格调,另一方面可以进新鲜的表达方法。 Literal translation refers to an adequate representation of the original. When the original coincides or almost tallies with the Chinese language in the sequence of vocabulary, in grammatical structure and rhetorical device, literal translation must be used. Free translation is also called liberal translation, which does not adhere strictly to the form or word order of the original.(郭著章) 直译法是指在不违背英语文化的前提下,在英译文中完全保留汉语词语的指称意义,求得内容和形式相符的方法。

成语,俗语,歇后语摘抄

熟语汇总――成语,俗语,歇后语1 成语篇 日常生活中极容易用错的成语知识 1 曾几何时:表示“过去没有多久”。常误用为“曾经”“不知何时”。 2 不学无术:指“没有学问才能”。不能在其前加上“整天”“整月”等修饰词语。“学”为名词,常误作动词。 3 不可理喻:指“无法用道理使之明白”,常误用为“不可思议”。 4 不以为然:指“不认为是正确的”。常误用为“不以为意”,表示“不放在心上”“无所谓”。 5 守株待兔:贬义词,指“不主动努力,心存侥幸,希望得到意外的收获”,常误来形容公安干警的机智。 6 耳提面命:褒义词,形容师长殷切教导。常误用为贬义词。 7 不忍卒读:“不忍心读完”,形容文章的“悲”。常误用为形容文章写得不好。 8 鼎力相助;敬词,指对别人对自己的帮助。常误用为表示自己对他人的帮助。 9 蹉跎岁月:指虚度光阴。常误用来形容“岁月艰难、艰苦”。 10 名噪一时:指在当时很有名声。常误用为贬义词。 11 始作俑者:指某种坏风气的创始者。常误用为贬指。 12 不胜其烦:贬义词,指不能忍受其烦琐。常误用为“不厌其烦”。 13 脑无城府:指为人坦率,褒义词。常误用来形容“贬义词”,贬义词。 14 身无长物:指人贫困。常误用来形容没有特长。 15 目无全牛:指人的技艺高超,得心应手,易误作缺乏整体观念。 16 鬼斧神工:形容人的制作技艺高超,常误用为形容自然景观。相类似的还有“巧夺天工”。 17 求全责备:指对人苛求完善,后面不能带宾语,与此类似的还有“漠不关心”。 18 充耳不闻:塞住耳朵不听,形容不愿听取别人的意见。易误用为形容人专心,没有听到。 19 瓜田李下:形容容易引起嫌疑的地方。易误用为形容田园生活。 20 卓尔不群:形容非常优秀,超出常人。易误用为形容人的性格。 21 出神入化:形容技艺高超。易误用为形容听得出神。 22 登堂入室:比喻学问技能由浅入深,循序渐进,达到更高的水平。易误用为“进入”。 23 如坐春风:形容受到良好的教化。与“景物”无关。 24 对簿公堂:在公堂上受到审问。易误解为“争论,明辨是非”。 25 相敬如宾:特指夫妻相敬相爱。另有“举案齐眉”。 26 走马观花:比喻粗略地观察事物,强调过程,易和“浮光掠影”相混。后者指印象不深刻,强调结果。 27 师心自用:形容固执已见,自以为是。易误用为“善于学习借鉴,为我所用”。 28 安土重迁:安居故土,不愿随便迁往别处。易理解相反。 29 罪不容诛:形容罪大恶极,与“死有余辜”同义。易误解为罪行还没有达到被杀的程度。 30 屡试不爽:屡次试验都没有差错。易误解为“没有成功”。

九年级英语unit课文翻译

九年级英语u n i t课文 翻译 Document serial number【KK89K-LLS98YT-SS8CB-SSUT-SST108】

unit3 Could you please tell me where the restroom are ? sectionA 2d 何伟:这就是欢乐时代公园——我们这座城市最大的游乐园。 爱丽丝:就要玩各种游乐项目了,我好兴奋呀! 何伟:我们先玩那样呢?有太空世界、水世界、动物世界…. 爱丽丝:在我们决定前,麻烦你先告诉我哪儿有洗手间吗? 何伟:什么?休息室?你想要休息了?我们可还没有开始玩呢! 爱丽丝:不是的,我不是指休息的地方。我是说…..你知 道,一间洗手间或卫生间。 何伟:嗯….那么你是指….卫生间吗? 爱丽丝:对啦!不好意思,也许中国人说英语不常用 restroom这个词。 何伟:就是的,我们常说toilets 或washroom 。不过,厕所在哪里。 爱丽丝:知道了,我一会儿就好! 何伟:没问题,你不必赶的。 Section A 3a 欢乐时代公园————总是欢乐时光 [ 爱丽丝和何伟在太空世界] 爱丽丝:我不知道我们接下来该去哪里。

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