Masterpieces in Process Chemistry
Richter
Selected Syntheses Discussed: Me HO O
Me
OH
O
NH2
HN
O
Lipitor Pfizer
H S
O
Ketorolac Syntex
NH
H
CO2H
F
O
N H
N
OH Me
MeHN
O OH
O Me
Tamiflu Hoffmann-LaRoche
CN
N
O
N
CF3 O
MIV-105 Chiron
SB-273005 GlaxoSmithKline
OH
H
CO2H
O
O
ERa-SERM Merck
Cortisone Merck
N
O
N
N
O N H
N
O O
tBuHN Me
NH
OH
Ph H N
N O
O
Indinavir Merck
Me N
Cl
Cl
N
O
Linezolid Pharmacia
NH2•H3PO4
N H
OAc
Me
F
CO2Et
AcHN
O
H
Biotin Tanabe Seiyaku Co.
EGFR Irreversible Inhibitor Pfizer
S
Me O
CO2H
N
HO
Me
O
H
O HN
N
NH N
Cl N
O
Zomig AstraZeneca
N
F HN
N H
Me
Discodermolide Novartis
OH
O
O
Me
O
NMe
O
F
OH
Me
H N
CO2
HO
Me
Me
HO Me
Me
H
O
Me
11/3/04 Group Meeting
O
O MeHN
OH N O
O
Me
Claritin Schering-Plough
N
S
Amerge GlaxoSmithKline
N H
N H
Clarinex Schering-Plough
Masterpieces in Process Chemistry
Richter
11/3/04 Group Meeting
Selected Syntheses Not Discussed: H
HO MeO O AcO Me
S H
O
H
OMe
NH HO
Cl Me
O
H
OH
N CO2Me
O
H
NHMe
H F3C
NH3+
H
Me
N
O
See Jeremy Richter, Baran Group Meeting, January 2004
H N
N
N O
N Me
FTI Candidate Pfizer
O
O H
H Me H
H
H
O H
H
O
O
H
H
O
H O
H
O O Me O
Halichondrin Kishi
H
O
H
O H
H
1. This is by no means a comprehensive sampling of the many masterpieces in process chemistry.
3. Some of the syntheses not discussed above were not done so because they were either not actual process routes (Ecteinascidin 743, Halichondrin) or I was unable to locate the relevant literature in time. 4. To give this topic the credit it deserves would require the publication of Classics in Process Chemistry.
OH MeN HO
H
2. Process syntheses are very difficult to locate and decipher, since most of the relevant literature is burried in patents and the words "process scale" do not appear in the titles.
CO2–
Thienamycin Merck
Prozac Eli Lilly
Me
Disclaimers:
OH O
O
H
HO
Indoxacarb DuPont
Ecteinascidin 743 Corey
H
O
HO HO
H O
O
N N
Me
N O
OCF3
O
H N
H
CO2Me
Me
Cl
S
Me
N NMe
Zyprexa Eli Lilly
5. Many of the syntheses presented here are wonderfull full papers that delineate the entire conception process along with problems encountered along the way. I recommend these papers for more information. Partial List of Transforms: Zhao olefination, Parikh-Doering oxidation, Still-Genari olefination, NozakiHiyama coupling, Evans-Saksena reduction, Kagan oxidation, Ullmann reaction, Strecker reaction, Moffit oxidation, Fukuyama coupling, WohlZeigler bromination
Masterpieces in Process Chemistry
Richter (–)-Discodermolide
Me
O
Me
H
Me
NH
Me PMBO
Me
HO O
Me
Me Me
HO Me
OH
OH
O
11/3/04 Group Meeting
NH2
CCl3 PMBO
PPTS, DCM > 98%
CO2Me
LiBH4, THF
Me
[LAH worked well but filtration = 24 hrs]
O
OH
1. Non-taxane microtubule stabilizing agent (most potent known). 2. Small amounts available naturally and must be harvested by manned submersibles. Fermentation has not been successful so all material must come from total synthesis. 3. Currently in phase I clinical trials. 4. Previous syntheses: a. Schreiber, JACS 1993, 115, 12621; ibid. 1996, 118, 11054 b. Smith, JACS 1995, 117, 12011; OL 1999, 1, 1823; ibid. 2000, 2, 1983; JACS 2000, 122, 8654 c. Myles, JOC 1997, 62, 6098 d. Marshall, JOC 1998, 63, 7885 e. Paterson, ACIEE 2000, 39, 377; TL 2000, 41, 6935; JACS 2001, 123, 9535; OL 2003, 5, 35. 5. Novartis Process Synthesis: a. Drew heavily upon the Smith and Paterson approaches b. OPRD 2004, 8, 92-130 "One major problem associated with a synthesis of this length is the proper laboratory examination of the later reactions in a sequence. Initially, there are no answers to these supply problems; one just has to run the small-scale reaction and hope that on transfer to larger scale the reaction proceeds as expected. . . . On a positive note, this project was a first for Novartis, and its progress was avidly followed by the entire department who were all interested in the "disco". The success of this project and its chemistry paves the way for other, perhaps even more complex, natural products to be prepared for early-phase clinical evaluations and sends a positive message to both the isolation and synthetic academic community and possibly other pharmaceutical companies that: "your work need not just be of academic interest" and it may be worth taking a few risks. A total of 43 chemists participated in the concept of the synthesis, experimental design, and execution. . . . The hybridized Novartis–Smith– Paterson synthetic route that resulted in the preparation of 60 g of a structurally complex molecule containing 13 stereogenic centers is a crowning achievement to all those who participated in this endeavor. The option of optimizing the present synthesis further or replacing with a better one is a topic of our ongoing studies, and we are confident of climbing this mountain as the situation demands."
> 98%
CO2Me
Bn Me Me PMBO
OH
O
N
TEMPO, Bleach,
Me
DCM 100%
O
O O
PMBO
Bu2BOTf, TEA, > 75%
[Swern not amenable for large scale – stench]
[46-55% on 20-25 kg scale] Me NH3
Me
Me
PMBO
Xc OH
i. LiOH H2O2
O
N
MeO
Me
OMe
Me O
N
OMe
MeNHOMe
Me
Me
Me N
PMBO
85% OH
O
N
N OMe
O
i. HCl ii. iBuOCOCl iii. MeNHOMe 75-80%
N
PMBO
O OH
[First purification: crystallization]
N
Me
PMBO
ii. (R)-Phenylethylamine 84%
Cl
ii.
Me
i. LiOH, H2O2, MeOH
OH
O
OMe
Masterpieces in Process Chemistry
Richter Me
Me
PMBO
NMeOMe OH
Me
TBSOTf, 2,6-Lut.,
Me
PMBO
NMeOMe
Tol., 0 ºC 90%
O
Me
TBSO
Me
Me
PMBO OH
Me
DDQ, Tol.,
NMeOMe
O
11/3/04 Group Meeting NMeOMe
M.S., 0 ºC 61%
O
O
O
O
[Chromatographic purification – 12 kg] [DIBAL-H reduction worked but –78 ºC was unacceptable] [Chromatography required]
Me
Me
Name?
I
NaHMDS, THF,
PMBO
Me TBSO
I
(15:1 cis:trans, 31%)
Ph3P
Me
I
TBSO
Me
TBSO
Me
Me
Bn Me
OMe N
O
O
O
OH
O
O
i. LAH, THF ii. Bu2BOTf, TEA, –78 ºC to –10 ºC,
O
Bn Me
85% [Crystalline]
I Ph3P
Me
Me
Me
Me
NMeOMe TBSO
Name?
O
O
O
O
Me
OTBS
I
Ph3P, I2, imid.,
O
O
OTBS
[Chromatography Required] OMe
24% overall
Me
NMeOMe O TBSO
Me
Tol., RT, 90%
i. MeMgBr ii. SO3, Py, DMSO Me
Me OH
OMe Me
O
O
Me
O
ii. TEMPO, PhI(OAc)2
N
OMe
Me
t NMeOMe i. H2, Pd/C, BuOH
O
i. TBSOTf, 2,6-Lut, 100% ii. LiBH4, THF –30 ºC to RT, 60%
Me
NaHMDS, I2 Me
Me
PMBO
[Chromatography required] [No larger than 2.5 kg]
PMBO
Red-Al, Tol., –20 ºC 68%
O
66% overall
[Chromatography Required]
Masterpieces in Process Chemistry
Richter
Me
Me
i. tBuLi, 9-MeOBBN, THF, –78 ºC ii. Cs2CO3, DMF, Pd(dppf)2Cl2, RT
Me
I PMBO
Me
TBSO
I
Me
O
O
Me O
[problems with commercial purity of (+)-DIP-Cl]
OMe Me
i. DIBAL–H, 92% ii. SO3, Pyr., DMSO, 93%
PMBO
Me
O
MeOMeN
Me PMBO
Me
Me
Br
OTBS OPMB Me
Me
Me PMBO
iii. KHMDS, 18-c-6, 76% O F3CH2CO P F3CH2CO
Name?
TBSO
CO2Me Me
MeO2C
Me
Me
Me
Me
Me TBSO
OTBS OH Me [Chromatography required]
O
Me
Me
OTBS OCONH2 Me
TBSO
4:1 dr, recyclable
Me4N+(OAc)3BH, 73%
Name?
Me
Name? HO Me
Me
ii. KOH
i. DDQ, H2O, 88% ii. PhI(OAc)2, TEMPO
O TBSO
Me
O
OMe
TMS
TBSO
Me
[Chromatography required on reverse-phase silica]
i. CrCl2,
O
Me
MeOMeN
Me O TBSO
TBSO
Me
(+)-DIP-Cl, TEA, 55%
HO Me
Me
Me
Me
+
Me
Me
OTBS O Me
Me
OTBS OCONH2 Me [Chromatography required]
TBSO
TBSO
Me
Me Me
Me
Me
11/3/04 Group Meeting
MeOMeN Me
OH
Me
Me OTBS OCONH2 Me [Chromatography required]
Me O TBSO
Me
Me
TBSO
HCl, MeOH
Me
Me
OTBS OPMB Me
HO
81%
[Chromatography required]
i. CCl3CONCO; Na2CO3, MeOH, 100% ii. DIBAL–H, DCM, –78 ºC iii. PhI(OAc)2, TEMPO, 80%
O
O
Me Me
OH
Me
Me
H
Me
Me
Me
OH
O
OH
NH2 O
discodermolide [ > 60 g produced]
39 steps, 17 chromatographic purifications, 20 months 7 problematic steps identified and being optimized
Masterpieces in Process Chemistry
Richter
EGFR Irreversible Inhibitor
O
N
HN
1. Treatment of solid tumors. 2. Inhibits Epidermal Growth Factor Tyrosine Kinase. 3. Process synthesis – Rober Hughes, Pfizer, Gordon Research Conference Presentation.
F
NH2
NH
NH2 N
[Observed losses to dechlorination]
1% Pt/C, THF, H2
O2N
NH
F N [6.5:1 regioselectivity]
80% from EtOH < 0.2% deschloro
N O
HN O2N
Cl N
F
COCl
TEA, EtOAc, 51%
O
HN
HN
Last step was optimizable, but for legal reasons they had to develop:
O
i. Ac2O, 85% ii. 1.5% Pt/C, H2, THF, 99%
N
COCl
iii. TEA, THF, 0 ºC; NaOH, 80% iv. MeSO3H/AcOH/THF; NaOH, 90%
Cl N
[2 recrystallizations]
Cl
Could not improve
N
F
86% Cl
O
[Yield loss]
i. SOCl2, 98% ii. TEA, iPrOH,
H2N
Cl N
[Material still lost in cyrstalization]
Used DMF instead of HOAc for Recrystallization 74%
F
HN H2N
ii. HOAc, 57%
F O
F
H2, 99%
i. 65% HNO3/ H2SO4, 70 ºC, 81%
O
F
O
Ra-Ni, THF
Improved Route
•AcOH
CH3OCH2CH2OH 98%
N
into one pot, 95%
O
H
N
Combined 3 operations
N
Cl N
O
[83% after recrystallization]
N
Problems
O2N
KOtBu, THF 98%
Cl N
O
CO2H
OH HN
HN
NH
F
O F
Initial Route
11/3/04 Group Meeting
N N O
Final: 8 steps (3 pots) 55% overall yield produced multikilo's
Masterpieces in Process Chemistry
Richter
11/3/04 Group Meeting
2nd Generation Route
Ketorolac O
O N
O
Br2
H N
H CO2H
DMF, 80 ºC
H N Br
0 ºC
O O
Br
1. 2. 3. 4. 5.
Non-steroidal antiinflammatory drug (NSAID). Powerful antiinflammatory and analgesic activity. 10 mg equiefficacious with morphine (10 mg) for post-operative pain. 10 mg equiefficacious with aspirin (650 mg) for postpartumpain. 10 mg equiefficacious with acetaminophen (1 g) or acetominophen (600 mg)/codein (60 mg) combination. 6. Syntex development: Muchowski, Adv. Med. Chem. 1992, 1, 109.
O O
Br
i. NCS, DMS DCM, –30 ºC
H N
PhCONMe2 POCl3, DCE
H N
i. HO– ii. H2, Pd/C,
Mechanism? O
NaH, DMF; 55 ºC,
SMe
O
O
O O
O
O O
O N SMe
MeO2C
i. mCPBA ii. MeOH, HCl
ii. NaH, DMF, 75 ºC
Br
D
H N
N
CO2Me CO2Me
Br
SMe
ii. D, 60% O
O
i. MeOH, HCl
N
1st Generation Route
O
O O
O
O
CO2Me
O
i. NaH, DMF, 85 ºC ii. NaOH
N SO2Me
Ketorolac, 21% from pyrrole racemic
MgO iii. HCl
Ketorolac, 47% from benzoyl pyrrole racemic
3rd Generation Route Begins from Pyrrole and proceeds in 45% overall yield: See US Patent 6,197,976 New Chemistry Discovered: 1. Selective substitution of pyrrole at C–3 when protected as N–Silyl. 2. Acid induced isomerization of C–2 substituted pyrroles to C–3. 3. New routes to pyrrole-2-carboxaldehydes. 4. New routes to acylpyrroles. 5. Mild reduction of acylpyrroles to alkylpyrroles. 6. Conversion of acylpyrroles to acylpyrrolidines. 7. First reported intramolecular carbenoid addition to a pyrrole nucleus.
Masterpieces in Process Chemistry
Richter
11/3/04 Group Meeting
ERa-SERM HO
BnO
S
OH
S O O
HCl, 92%
O
N
OBn
O
I
S
OBn
BH3•THF 10 ºC 88%, 99% ee
Name?
BnO
Mechanism?
CuI, K2CO3, 2,2'-bipyridyl, 140 ºC
O BnO
OBn
O
i. BnBr, NaI, K2CO3, 84% ii. NaOH
I
S+
BnO
Cumene hydroperoxide
MgBr
OMe
S
O–
D-DIPT Ti(OiPr)4
Mechanism? Me
BnO
I
1. SERM = selective estrogen receptor modulator. 2. Potentially useful for the treatment of bone loss, cartilage degeneration, endometriosis, uterine fibroid disease, hot flashes, increased levels of low-density lipoprotein cholesterol, cardiovascular disease, obesity, incontinence and cancer. 3. Synthesis: Merck, PNAS, 2004, 101, 5776. HO
PhPOCl2
MeCN, 90%
N
O
(H2N)2CS,
OBn
O OH
O
O
S
N OH
I
SH
+
O
OH I
BnO
BnO
S
OBn
TMSI O
81% OBn
PhMe3N+Br3– DME, 100%
O I
80%
Br
92%
O
OBn
88%
O I
HO
S
OH
O O
N
ERa-SERM 8 steps 37% overall yield
N
Masterpieces in Process Chemistry
Richter Biotin
O S NH
H
H S
1. 2. 3. 4.
NBn HCl, 90 ºC H 95% NHBn
O
i. PhOCOCl, NaOH, NH2•HCl H2O, Tol., RT H
S
NBn H
ii. BnCl, NaOH, DMSO, H2O, RT
CO2H
83%, >99% ee
S
NBn H O
86%, >99% ee
i. H2O2, K2CO3, DMSO/DCM
Pd/C, THF,
ii. DCC, TFA, Pyr., DMSO, EtOAc, 50 ºC
94%
Name?
i. H2 (0.9 MPa), Pd(OH)2/C, MeOH, H2O;
ii. H2O, filter iii. HCl
S
NaCN, 8–20 ºC; NaHSO3, NaCN
O NHBn + H NHBn
NC
O
S
NHBn H NHBn NC
100% 11:1 syn/anti
O
O NBn + H NHBn
H2NOC
93%
S
DMF NHBn H 120 ºC NHBn
H2NOC
7%
BnN
NBn
H
H S
91%
O
O
CO2Et BnN
NBn
H
H
Tol, DMF
CO2Et
S
O
NaOH, 90% ii. MeSO3H, mesitylene, 74%
HN
NH
H
H S
H S
Name?
Zn
i. NaBH4, H2SO4, THF, D
O
i. NaHSO3, EtOAc ii. BnNH2, DCM;
S
CO2H SH
NBn
H
CO2Et
I
Name? O
BnN
10–60 ºC 93%
H
H
IZn
CO2H
NBn
H
H2NOC
CO2H
Important in human nutrition and animal health. > 80 tons produced synthetically anually. Synthesis: Tanabe Seiyaku Co., Chem. Eur. J. 2004, ASAP. For a comprehensive review of Biotin syntheses see: Ryan Shenvi, Baran Lab Group Meeting, July 2003.
HS
BnN
O
DCC, TFA, Pyr.,
DMF, 90 ºC;
O HN
O
11/3/04 Group Meeting
H
biotin 12 steps, 39% overall
CO2H
O
Masterpieces in Process Chemistry
Richter Cortisone
OH
OAc O
Me
O
Me Me
Me
Me
OH
O
Br O
i. Br2, CHCl3
O
Me Me
i. PhMgCl
CO2Me
Me
ii. Na2Cr2O7 CrO3, acetone
CO2Me
Me
ii. H2O, CHCl3
HO
Synthesis at the time was meant to provide large quantities to test. Starting material readily available from cow bile. Work done in the early 1950's without modern spectroscopy. Work done in less than 2 years. Process synthesis: Merck, OPRD, 2004, 8, 708.
Me
i. HBr, CO2Me CHCl3
Me
1. 2. 3. 4. 5.
11/3/04 Group Meeting
ii. HOAc, D
75.5% 61.6% from SM
O
Me OH
Me
OH
Me CO2H
Me
MeOH
CO2Me
95.5%
iii.
OH
Me CO2H i. MeOH,
91%
HO–;
H+
ii. H2, Pt0 HO
iv.
H+
SeO2 worked in 1 step but needed in Korean War electronics
Me
Me
HO
i. Br2, MeOH/PhH ii. NaOAc, DMF
Me
Me
O
Ph O
Ph
87%
Me
i. HBr
Me
Me Me CO2Me
Me Me
i. Na2Cr2O7, H2SO4
Me
Ph
hn; D Name?
Ph
92.7%
AcO
O
NBS, PhH,
Me Me Ph
ii. Ac2O
Br
Me
EtO2CO
O
94%
HO
ii. CrO3
Me
Me
HO
i. EtOCOCl, Pyr.
O CO2Me
H2SO4
O
Me Me
Br
Me
Ph
ii. Zn, HOAc
87.4% AcO Me
"As interesting as was the kinetics of acetic acid formation during enol acetylation or peracid uptake during the oxidation and despite the nice data plots, they taught little about minor byproducts or overreaction."
O
Me
O
DNBS, Ac2O;
Me
MPPA; NaOH AcO
92% [DNBS = dinitrobenzenesulfonic acid] [MPPA = monoperphthalic acid]
Masterpieces in Process Chemistry
Richter Me O
OH
Me
HO
AcO
O
Me
i. Br2, MeOH, PhH ii. KOAc, HOAc, NaI iii. DDH, acetone iv. Zn, HOAc
94%
O
Me
O
Linezolid
OH
Me
O N
O
86% 52.6% from ether
[DDH = dibromodimethylhydantoin]
O
F
N
"With benzene, we actually considered it beneficent in that carbon tetrachloride was a known liver toxin. Little did we know at the time that we were exchanging it for what would many years later be labeled a carcinogen!" AcO
i. Br2, CHCl3, HOAc
Me
O
H2NCONHNH2
Me
ii. NaBr, acetone
O Me
H2NOCHNN
F
95%
[step 2 used to convert O all side products to the Br desire product] "A great deal of development was still required as the demonstration with an incompletely developed process was initiated in the new plant. Some improvements were made on an ad-hoc basis, at times prematurely, with production at sub-optimal performance better than no production at all. For better and for worse, such a modus operandi is no longer practiced, courtesy of FDA and cGMP regulations." Me
AcO
O O
OH
O
NH
"Product elegance has long been an ethereal objective of ethical pharmaceutical companies; it is sometimes an expensive one. Planning for the last step has to include concerns of color and appearance as well as chemical purity. It is annoying to some synthetic chemists to see a difficultly won, elegant, white crystalline material subjected by pharmacists to granulation, sometimes coloration, and compression to an unnatural form."
K2CO3 F
HO H
N
i. Cl
F
ii. KOtBu iii. LDA
NHCbz
CbzCl,
N
O
OH
O
ii. Pd/C, H2
NO2
O
92% 87.4% from triketone 28.3% overall
NH
i.
F
Me
HCl CHCl3
Me
Me
H
O
AcO
O O
1. Active against gram-positive and gram-negative bacteria with potency in the 2-4 mg/mL. 2. Synthesis: Pharmacia/Pfizer, ACIEE, 2003, 42, 2010, US Patent: 5837870.
O OH
11/3/04 Group Meeting
NH2
O OH
90% Overall
N F
O N H
O OH
O N
O
TEA, F
N
NsCl 85% Overall H
O
i. NH4OH, MeOH, 45 ºC ii. Ac2O, 85% ONs
linezolid 9 steps 65% overall yield
Masterpieces in Process Chemistry
Richter
i. tBuOAc, H2SO4, 90%
Indinavir N
OH
tBuHN
CN
O
O
i. pyroglutamic acid resolution with recycle, 47%
HN
N
OH
H N
N
N
N
Ph
NH
ii. H2, Pd(OH)2, 95% Me Me Ph
1. HIV Protease Inhibitor. 2. Synthesis: Merck, Chimia, 1997, 51, 306. Narendra Ambhaikar, Baran Group Meeting, July 2004.
11/3/04 Group Meeting
O
CONHtBu
ii. Boc2O, KOH, 80%
BocN
i. MeOH, D ii. HCl(g)
O
N
N
O
O
tBuHN
(S,S)-MnII(salen)Cl NaOCl, P3NO
Mechanism?
87% ee
N
Oleum,
tBuHN
94%
99% ee Cl
iPrOAc,
NH2
NaOH, 70 ºC;
NH2
base
MsOH, 35 ºC, Me Me Me Ph
N Me Me Ph
O N Br
88%
H2SO4
OH
99% ee >50% yield
N O
N
Tartaric acid, OH
OAc
OH
O
O
OH COCl
H N
N
MeCN, H2O
OH
enzyme
Ph
OH
LHMDS, –15 ºC 94%
O
i. NIS, H2O, NaHCO3, 91% ii. NaOMe, 100%
Ph H N
N
N O
OH
tBuHN
O
O
indinavir 75% over 3 steps >32% overall
OH
O
Masterpieces in Process Chemistry
Richter
OH
Lipitor
HO HO
CO2
HO
O
CO2K
CaCO3, K2CO3
HO OH
N
OH
Me
Hypolipidemic. Number one selling drug of all time (Natural product inspired). Synthesis: Bruce Roth, Pfizer, Prog. Med. Chem. 2002, 40, 1. Largest competitors: HO
Me
Me
Mevacor HO
Me
Me
O
O
H2, Ra-Ni, CO2tBu
NC
HO
H
O Me
Me
HO Me O
Me
H
CONHPh Me Me Me
Me
O
HO
Zocor
Pravacol
HO F
Me
Me
O
O CO2tBu
H2N
Mechanism?
Me Me
MeOH, 95%
CO2Na
O O
O
CO2tBu
iii. TBAF, HOAc, THF or: 3 equiv. LiCH2CO2tBu
ii. Me2C(OMe)2, MeSO3H, 65%
Me
O
NC
i. NaBH4, Et2BOMe, MeOH, –90 ºC
H
OH
Mg(O2CCH2CO2tBu)2
O O
i. TBSCl, imid., 4-DMAP ii. NaCN, DMSO
CO2Me
O
O
CO2Me
Br
i. NaOH ii. CDI,
OTBS NC
OH
H2, Pd/C
Br
O
Me
CO2Me
Br
NH
Me
MeOH
OH
Me
F
O
HBr, HOAc,
OH
H2O2,
O
HO
1. 2. 3. 4.
11/3/04 Group Meeting
Bn N+ Cl– S
F
O Me
TEA O
O
Me CONHPh
Masterpieces in Process Chemistry
Richter F
O
+
Me
Me
O
O
Me O
Zomig NMe
O O
pivalic acid 1:4:1 Tol.:heptane:THF D, 75% Me
H N
CO2tBu
H2N
Me CONHPh
O
CO2tBu
Me O
N H
1. Used to treat migraine headaches. 2. Synthesis: AstraZeneca, US Patent 6084103, 6160123, Li, J.J. Contemporary Drug Synthesis, Wiley, 2004. i. Na2CO3, H2O, EtOAc; ClCO2Bu ii. H2, 5% Pd/C, EtOAc, BuOH, 30–50 ºC
ClH•H2N MeO2C
NO2
Me
F
11/3/04 Group Meeting
N
iii. NaBH4, BuOH, 35 ºC iv. NaOMe, MeOH, BuOH, 85 ºC
Me NH
i. NaNO2, HCl, 0 ºC ii. Na2SO3, H2O, 0–60 ºC
O
iii. reflux, 3 hr OEt EtO
NMe2
CO2
HO
Me
F N
Me NH O "...produced stereochemically pure atorvastatin calcium in a convergent, commercially viable manner which accomplished the original vision for the synthesis developed in discovery chemistry, but was reduced to practice in chemical development."
H N
NMe2
O O
N H
No yields given One-pot procedure
O O
iv. 10% EtOH/EtOAc
HO
H N NH2
precipitated upon cooling
Masterpieces in Process Chemistry
Richter Tamiflu
MIV-105 Me
F
Me O
N H
1. Potent inhibitor of influenza neuraminidase at nanomolar concentrations. 2. Synthesis: Hoffmann-LaRoche, Chimia, 2004, 58, 621.
1. Non-nucleoside reverse transcriptase inhibitor. 2. Synthesis: Chiron, OPRD, 2004, 8, 353. i. SOCl2, DEA, 0 ºC, 86%
3 steps CO2H
70–80% Me
HO
CO2Et i. Et3SiH, TiCl4
O
OH
ii. BuMgNiPr2, THF, D; I2, THF, 5 ºC, 56%
5 steps HO
Me
O
OH
Me
i. NaN3, NH4Cl, DMF, 85 ºC
Me Me
O
ii. Ac2O, Pyr. 35%
i. NaN3, NH4Cl, CO2Et EtOH, 65 ºC
HN
ii. PMe3, MeCN, RT
iii. MeI, K2CO3, 97% iv. (CH2OH)2, pTSA, PhH, 86%
Me O
iii. HCl, 78% iv. TsOH, EtOH, D, 93%
O
i. EtCOCl, Pyr., 100% ii. AlCl3, 88% Mechanism?
F
40–45%
OH
Me
F
80%
OMs
i. HNO3, D, 92% ii. IPA, BnHN Ph NEt2
I
ii. NaHCO3
OH CO2H
HO
N
Me
O
NH2•H3PO4
CO2H
N H
OH
AcHN
HO
CN
O
CO2Et
11/3/04 Group Meeting
O
i. HCl, dioxane, H2O ii. LiOH, MeOH, H2O iii. HCl
O
Me
i. BuLi, THF, –78 ºC ii. ZnBr2, –65 ºC CO2Et
iii. Pd(OAc)2, (ArO)3P, –65 ºC, 85%
OMe
O
CO2Et
O
F CO2Et
I
OMe
Name?
Me O
Me
Me O AcHN
Me CO2Et
O
i. Lindlar, H2 ii. H3PO4, 80%
F
Me CO2Et
CO2H
NH2•H3PO4
Tamiflu 35% from Shikimic acid 20% from Quinic acid
O
Me
H2N
N H
N
N H
N
OMe
CN
iii.
CN
O
i. TEA, EtOCOCl ii. NaN3; D
OMe
AcHN
N3 [A series of studies was undertaken to improve the efficiency and safety of this route, through the replacement of the azide chemistry, as well as beginning with more cost effective starting materials.]
F
O
Me
BCl3, DCM, 52%
MIV-105 27% overall yield
Masterpieces in Process Chemistry
Richter Amerge
11/3/04 Group Meeting
Claritin and Clarinex
Me N
Cl O MeHN
N
S
N
N H
N
1. Used to treat migraine headaches. 2. Synthesis: GlaxoSmithKline, J. Med. Chem. 1995, 38, 3566, Li, J.J. Contemporary Drug Synthesis, Wiley, 2004. O
Me N
NMe Br
i.
MeHN
KOH, IMS, D, 94%
Br
O S
TEA, DMF, 85 ºC ii. HCl, 89%
Me N
MeHN
H2, Pd/C,
O
N H
Me N
CN
DMF, H2O, MeOH, 90%
MeHN
ii. nBuLi, THF, –40 ºC, NaBr
i. POCl3, 89% Cl ii. BrMg O
N
NMe
THF, 50 ºC; HCl, RT, 89%
NHtBu
Cl
Cl
Cl
O
O
Me
i. tBuOH, H2SO4 75 ºC, 97%
Me N
S
O
1. Antihistamines. 2. Synthesis: Schering-Plough, J. Org Chem. 1989, 54, 2242, Li, J.J. Contemporary Drug Synthesis, Wiley, 2004.
N H
O
N H
O
Pd(OAc)2, (o-tolyl)3P,
O N H
Cl
O
S N
i. HF, BF3, 92% ii. TEA, Tol.,
O
N H
Amerge 75% overall yield
Cl N
80 ºC, 73% Me
N Me
O
COCl
N O
Cl N
KOH, H2O
clarinex 47% overall yield
EtOH, D, 91% N H
O
Me
claritin 52% overall yield
Masterpieces in Process Chemistry
Richter SB-273005 MeHN
N
O
CF3
N
O CO2H
H
1. Vitronectin receptor antagonist. 2. Synthesis: GlaxoSmithKline, OPRD. 2004, 8, 738.
HO
i. Br2, DCM, 65% ii. itaconic acid, TEA,
O
HO
Pd(OAc)2, (o-tolyl)3P, Bu4NBr, MeCN, 80%
O
HO2C
CO2H
OMe
DCA, [RuCl2(R-BINAP)]2,
HO
TEA, H2, 60 ºC, MeOH, H2O, 84%
OMe
MeOH, D, 86%
HO2C H
HO
i. ZnCl2, MeCN, D,
O
ClH•H2N MeO2C H MeHN
N
CO2Me
H2SO4,
CO2H
HO
CF3
O
ii. NaBH(OAc)3, DMA iii. TFA, Tol., D, 72%
N
O
N
CF3 O
i. PPh3, DIAD, TBME ii. LiOH, H2O, THF, 50 ºC, 66%
CO2Me
H
OH MeHN
CF3
N
SB-273005 18% overall yield Last Reaction = 50 kg
H
CO2H
11/3/04 Group Meeting
