Chirality
C3, C4 and C6
Chiral Building Blocks
Samsung Fine Chemicals Co., Ltd.
http://www.sfc.samsung.co.kr
contact us!!
[email protected]
 [email protected]
 [email protected]
Pharmaceutical Fine Chemical 시장 분석 (1999년, 출처: ADL)
- 시장규모
- 성장율
- 가격
- 생산량
- 시장점유
- 품목 例
Basic
building blocks
Advanced
intermediates
Standard bulk
active compounds
30 ~ 40억 달러
60억 달러
120억 달러
매년 3% 성장
매년 10%이상 성장
매년 5 ~ 6% 성장
5 ~ 10$/kg
10 ~ 1,000$/kg
5 ~ 1,000$/kg
100 ~ 1,000톤/년
1 ~ 100톤/년
1 ~ 100톤/년
상위 10개 공급사가 상위 10개 공급사가 상위 10개 공급사가
전체 45% 점유
전체 25% 점유
전체 10% 점유
아미노산, 주석산,
사과산, HGB 等
7-ACA, 6-APA,
CHB, HTF 等
아스피린,항생제원제,
Generic 원제 等
세계의약품 및 카이랄 중간체 시장 현황
세계 완제의약 시장 ( $ billion )
세
계
의
약
품
및
키
랄
중
간
체
시
장
년 도
‘94
2000
2005
성장 율
시 장
256
370
490
6% 성장
완제의약 시장분포 ( %, 판매액 기준 )
‘80
‘90
‘94
2000
합성 키랄의약
3
9
17
34
천연 키랄의약
20
26
27
28
라세믹 의약
17
15
17
17
비 키랄의약
60
50
39
21
총 계
$100 bil
$190 bil
$260 bil
$370 bil
키랄
의약
합성 키랄의약 시장( $ billion )
년 도
‘90
‘92
‘93
‘94
‘95
2000
성장 율
시 장
18.0
29.2
35.6
45.2
55.0
126
20% 이상
키랄 중간체 시장( $ billion )
년 도
‘94
2000
2005년
성장 율
시 장
0.92
1.7
3.0
10% 이상
의약관련 정밀화학분야 환경
 FDA 정책변화 (1992년)
"Chiral 의약품은 Racemic과 Enantiomer를 다른 물질로 간주한다"
예 > (R,S)-Ibuprofen →(S)-Ibuprofen(1996년)
 입체이성질체가 있는 경우 하나의 이성체만 의약품으로 인정
 정밀화학제품의 60% →의약관련제품
 원료의약품의 70%→Chiral 의약품
 정밀화학제품중 Chiral 의약품의 비중 42%
 지속적인 Chirotechnology 확보가 필수조건
Chirotechnology의 분류(의약품분야)
Chiral Pool
Asymmetric
Synthesis
Bio Catalyst
원료
천연물
Chiral Ligand,
귀금속촉매 또는
광학분할제
효소
광학활성
도입방법
출발물질의
광학활성위치 활용
합성방법으로
광학활성위치도입
효소의 위치선택적
반응성 이용 도입
광학순도
매우 우수
(> 99 % ee)
우수
(95-99%ee)
매우 우수
(>99%ee)
개발측면
기술확보 용이
장시간 개발기간소요
장시간 개발기간소요
장치면
단순
촉매/Ligand/분할제
회수공정(고난도)
장치산업
파급효과
기술중심품목군
Down Stream 형성 가능
품목군형성가능
촉매별 공정개발要
1효소 1품목 적용
방법
The Chirality Pool
Carbohydrates
D-Sucrose, D-Lactose, L-Ascrobic acid, etc
Hydroxy acids
L-Lactic acid, L-tartaric acid, L-Malic acid
Amino acids
L-Glutamic acid, L-Phenylalanine, L-Prolin
Terpenes
(+)-Camphor, (+)-Limonene, (-)-Menthol
Alkaloides
Ephedrine, Quinine, Cinchonidine
Preparation of HGB
General Scheme
HO
HO
HO
O
OH
HO
O
HO
NaOH/H2O2
O
OH
OH
HO
HO
HO
OH + HO
ONa
OH
Step 1
OH
O
O
O
+ HO
ONa
D-Lactose
Step 2
conc. H2SO4
HO
HO
HO
HO
O
O
OH + HO
+
OH
OH
O
Extraction
HO
O
Chemical purity: c-HGB:85%(C), h-HGB:93%(C)
s-HGB:97%(P)
Optical purity: min. 99.7%
O
HGB
(S)-3-Hydroxy--butyrolactone
O
C4-Chiral Intermediate
C a rbo h yd ra te
V itam ni C
B
- o r reg a r rd
C h ira lP oo l
OH
CO 2R
-T a ka sa go
A s ymm e tr ci
H yd rog en a toi n
R
( u -B Ni AP )
HO
O
CO 2R
X
4 -subs t iu
t e
td
ace o
t ace ta e
t
B
- a ye r
S
-K
H yd rog en a toi n
RO 2C
O
S
- FC
C h ira lP o o l
O
M
- itsu b si h i
D
- ci e l
D
- a si o
Fe m
r en ta toi n
K
- a ne ka
R edu c toi n
M a lc
i A cdi
O
X
CO 2R
4 -subs tiu
t ted
ace o
t ace a
t e
t
RO 2C
CO 2H
OH
M a lci A c d
i m onoes e
t r
Lactose and oligosaccharide methods
Lactose → HGB
Starch → HGB
Starch
N
N = 30 ~ 6,000
+
N
N
Liquification by Enzyme
Maltodextrin
M = 3 ~ 50
N
+
M
M
Saccharification by Enzyme
Oligosaccharide
Lactose
M = 0 ~ 20
M
Ox./Cyclization
Oxid./Cyclization
HO
HO
O
O
O
O
HO
HO
HO
O
OH
OH
Patent No. US 6122122
Mechanism of base catalyzed, oxidative degradation of an amylose chain
OH
OH
RO
RO
O
OH
HO
OH
O
OH
O
O
OH
HO
OH
O
-
OH
O
OH
O
-
OH
O
OH
OH
HO
OH
O
O
OH
HO
H
O
OH
OH
OH
OH
O
OH
OH
O
HO
H
O
O
HO
OH
OH
HO
OH
tautomerization
OH
HO
RO
O
HO
O
O
O
OH
HO
OH
O
+
OH
*
HO
OH
H
O
OH
OH
H2O2
HO
O
OH
OH
OH
O
O
RO
OH
O
OH
+
*
HO
OH
*
O
OH
H
+
OH
OH
HO
O
O
OH
OH
OH
HO
Cyclization
O
O
Preparation of Ethyl (R)-4-Cyano-3-hydroxybutanoate
Route 1
OH
O
HO
OH
OH
H+/EtOH
Reduction
EtO
Step-1
O
OH
O
OEt
O
O
HO
OEt
Step-2
Malic acid
OH
HBr
O
OH
NaCN
Br
NC
OEt
Step-3
O
OEt
Step-4
CHB
Route 2
HO
OAc O
HBr/AcOH
O
O
OH O
EtOH
Br
OH
Step-1
Br
OEt
Step-2
HGB
OH O
NaCN
NC
Step-3
OEt
OH O
NC
OEt
Step-4
OH O
NC
H+/EtOH
OH
CHB
Patented Manufacturing Process of CHB by SFC
HO
OAc O
HBr/AcOH
O
O
Br
NaOH/H2O O
OH
Step-1
O
ONa
Step-2
HGB
NaCN
Step-3
OH
NC
O
H+/EtOH
ONa
OH
O
NC
OEt
Step-4
CHB
(S)-C3 chiral building blocks
(S)-N-(2,2-Dimethyl-1[1,3]dioxolan-4-ylmethyl)-acetamide(S-ADD)
(S)-N-(3-Bromo-2-hydroxy-propyl)-acetamide(S-BHA)
(S)-N-Oxiranylmethyl-acetamide (S-OMA)
(S)-3-amino-1,2-propandiol (S-APD)
O
OH
O
NHAc
Br
S-ADD
OH
O
NHAc
NHAc
S-BHA
S-OMA
HO
NH 2
S-APD
Applications:
1. Chiral building block for the syntheis of Zyvox®; WO9924393(Pharmacia & Upjohn)
O
O
NCO
N
OH
+
Br
O
NHAc
N
N
F
NHAc
F
O
O
O
O
N
H
N
OMe
+
O
O
NHAc
F
N
N
O
NHAc
F
2. Key intermediates for various drugs in Clinical trials
O
OH
NH
HN
O
O
H
N
O
O
O
N
H
F
LY-377604, Diabebtes
(Eli Lilly, Phase I)
O
NH 2
YM-992, antidepressant
(Yamanouchi, Phase II)
O
HCl
N
H
O
O
O
MKC-242, antidepressant
(Mitsubishi-tokyo, Phase II)
Preparation of Oxazolidinone
O
O
NH 2 +
(EtO)2C=O
OH
NH
OH
OH
1. TsCl/Py
N
O
NaOMe
2. NaN3/DMF
OH
O
O
O
1. P(OMe)3
N
O
N
NaOH/H2O/THF
O
2. HCl/H2O
N3
NH 2HCl
OH
O
Br
N
F
N
Ac2O
+
or
O
O
N
2 s tep
NH 2
NHAc
O
NHA c
N
O
F
NHA c
O
NHA c
(3R,5R)-(6-Cyanomethyl-2,2-dimethyl-[1,3]dioxan-4-yl)acetic acid t-butyl ester
O
O
O
NC
O
CDH
Application:
Key intermediate for the synthesis of Lipitor®; WO 9804543, EP 0330172(Pfizer)
O
NC
O
O
O
OR
O
HN
O
O
H2N
O
OR
O
F
O
OH
N
H
N
F
OH
CO 2-
Ca2+
2
(3S,5R)(6-Hydroxymethyl-2,2-dimethyl-[1,3]dioxan-4-yl)acetic acid t-butyl ester
O
O
HO
CO2t-Bu
HDH
Application:
Key intermediate for the synthesis of Crestor®
F
F
OH
N
Me N
N
iPr
SO2NME 2
CH 2O
OH
iPr
CO 2- Ca2+
N
N
N
2
Me
O
+
Ph3P
SO2NME 2
O
HO
O
CO 2R
O
CO 2R
Key Intermediate : (R)-& (S)-Epoxide
HO
O
O
MsCl
HBr
OAc O
OMs O
Br
HO
OH
OH
NaOH
NaOH
O
O
O
ONa
(R)-Epoxide
O
ONa
(S)-Epoxide
C3-C4, C6 Chiral building blocks
C3 Derivatives
RHA Derivatives
HO
HO
HO
N
H
O
N
O
RHPD
Ph
O
O
Br
NHA c
SADD
O
F
O
OH
O
CO 2N a
HO
Zyvox
NHA c
CO 2E t
RBHB
NHA c
N
N
SBHA
OH
RBPL
O
Br
NHA c
RHGB
O
OH
O
SOA
NH 2
OH
C l
O
RHA
O
HO
C3
NC
HO
HO
OH
HO
N
SBHPD
CO 2E t
O
Br
OM S
SHPD
BHBA
M e 3+N
CO
TMS
2
O
O
O
DAD
O
DBD
OH
M e 3+N
CO
2
O
N
H
2
Ac-LCT
Pilot/Laboratory
Atrovastatin
O
Ph
O
BPL
CO 2M e
HS
OAA
OH
H 2N
CO 2E t
AHB
N
H
O
MPL
BHAB Derivatives
LCT Derivatives
Commercial
CDH
N
C l- O A c
T a r M e +N
CO 2H
3
LCT-TAR
TOH Derivatives
CO 2E t
HO
-
LCT
Br
2
O
NC
HO
HPL
NH
O
BHB
CO 2H
OH
M sO
CHB
OH
TOH
OM S
N
H
O
HG B
OH
HO
Ph
Br
O
HTF
MCHB
CO 2E t
OH
HO
HMB
CO 2M e
OH
Laboratory
Product lineup
 HGB and Triol derivatives
Structure
Name
HO
O
O
(S)-3-Hydroxy-
-Butyrolactone
Specification
Chemical Purity ≥85%
93%, 97%
Optical Purity ≥ 99.8%
HGB
OH
HO
OH
(S)-(-)-Butane-1,2,4-triol
Chemical Purity ≥92%
Optical Purity ≥ 99.7%
Development Stage
Basic Intermediate for
Pharmceuticals & Chiral
Commercial
Chemicals (ex. Atrovastatin)
Key Intermediate for
Pharmaceuticals
Commercial
(VX-478 etc)
TOH
HO
(S)-(+)-TetrahydroO
Applications
furan-3-ol
Chemical Purity ≥99.8%
Optical Purity ≥ 99.7%
HTF
Key Intermediate for
Pharmaceuticals
Commercial
(VX-478 etc)
HO
N
H
S-HPD
(S)-Pyrrolidin-3-ol
Chemical Purity ≥98.0%
Optical Purity ≥ 99.5%
Key Intermediate for
Pharmaceuticals
(ex. Antibiotics)
Pilot
BHBA derivatives
Structure
Name
Specification
Applications
(S)-3-Acetoxy-4-Bromo-
Key Intermediate for
butyric acid
Chemical Purity ≥90.0%
Optical Purity ≥ 99.5%
(S)-4-Bromo-3-hydroxybutyric acid ethyl ester
Chemical Purity ≥95.0%
Optical Purity ≥ 99.5%
Key Intermediate for
OE t
O
(S)-4-Hydroxy-pyrrolidin2-one
Chemical Purity ≥95.0%
Optical Purity ≥ 99.5%
Key Intermediate for
(S)-1-Benzyl-4-hydroxy-
Key Intermediate for
pyrrolidin-2-one
Chemical Purity ≥ 95%
Optical Purity ≥ 99%
(R)-4-Cyano-3-hydroxybutyric acid ethyl ester
Chemical Purity ≥95.0%
Optical Purity ≥ 99.5%
Key Intermediate for
(3R,5R)-(6-Cyanomethyl-2,2dimethyl-[1,3]dioxan-4-yl)-ac
etic acid t-butyl ester
Chemical Purity ≥95.0%
Optical Purity ≥ 99.5%
Key Intermediate for
(R)-Butane-1,3-diol
Chemical Purity ≥ 95%
Optical Purity ≥ 99%
Intermediate for
OA c O
Br
OH
Atrovastatin
Development Stage
Commercial
BHBA
OH O
Br
BHB
Atrovastatin
Commercial
HO
N
H
Pharmaceuticals
Lab.-Pilot
HPL
HO
O
N
Ph
Pharmaceuticals
Lab.-Pilot
BPL
OH O
NC
OE t
Atrovastatin
Commercial
CHB
O
O
O
NC
OE t
CDH
OH
OH
Atrovastatin
Pharmaceuticals
Lab.
Lab.
LCT derivatives
Structure
Name
OH O
+
M e 3N
_
O
Specification
Applications
Development Stage
L-carnitine
Chemical Purity ≥99.8%
Optical Purity ≥ 99.8%
Dietary Supplement
Commercial
L-carnitine-L-tartrate
Chemical Purity ≥99.8%
Optical Purity ≥ 99.8%
Dietary Supplement
Commercial
LCT
OH O
M e 3N
-
O 2C
CO
2 HO
OH
+
OH
2
-
LCT-TAR
M e 3+N
OA c O
C lOH
Ac-LCT
Acetyl L-carnitine
hydrochloride
Chemical Purity ≥99.8%
Optical Purity ≥ 99.8%
Lab.
C3 derivatives
Structure
Name
Specification
Applications
NH 2
(S)-3-Amino-propane1,2-diol
Chemical Purity ≥ 98%
Optical Purity ≥ 99.5%
Key Intermediate for
NHA c
(S)-N-(2,2-Dimethyl-1[1,3]
dioxolan-4-ylmethyl)acetamide
Chemical Purity ≥ 98%
Optical Purity ≥ 99.5%
Basic Intermediates for
(S)-N-(3-Bromo-2-hydroxypropyl)-acetamide
Chemical Purity ≥ 98%
Optical Purity ≥ 99.5%
Key Intermediates for
(S)-N-Oxiranylmethylacetamide
Chemical Purity ≥ 98%
Optical Purity ≥ 99.5%
Key Intermediates for
OH
HO
C3
O
O
S -ADD
-blokers, antibiotics
Pharmaceuticals
Development Stage
Lab.-Pilot
Lab.-Pilot
OH
Br
NHA c
SB
- HA
O
NHA c
SO
- A
Zyvox
Zyvox
Lab.-Pilot
Lab.-Pilot
RHA derivatives
Structure
Name
Specification
(R)-3-hydroxy-
Butyro lactone
Chemical Purity ≥ 95%
Optical Purity ≥ 99.8%
HO
O
O
Applications
Development Stage
Basic Intermediate for
Pharmaceuticals &
Lab.
Chiral Chemicals
RHGB
OH O
Br
OE t
(R)-4-Bromo-3-hydroxybutyric acid ethyl ester
Chemical Purity ≥ 95%
Optical Purity ≥ 99%
Intermediates for
(R)-1-Benzyl-4-hydroxy-
Chemical Purity ≥ 95%
Optical Purity ≥ 99%
Intermediates for
RBHB
Pharmaceuticals
Lab.
HO
O
N
Ph
pyrrolidin-2-one
Pharmaceuticals
Lab.
RBPL
HO
N
H
R-HPD
(R)-Pyrrolidin-3-ol
Chemical Purity ≥95%
Optical Purity ≥ 99%
Intermediates for
Pharmaceuticals
(Antibiotics)
Lab.
Applications
No
Name
Structure
OH
Panipenem
S
N
O
N
NO
HCl
O
HC
3
CH 3
Antibiotics
Sankyo
Launched
(1993)
94M$/1999
2
O
O
N
H
Antihypertensive
N
O
HC
3
Stage
NH
OH
O
Barnidipine
Maker
H
H 3C
(Carbenin)
Therapy
Yamanouchi
Launched
(1992)
CH 3
O
O
OH
HN
2
Tosulfloxacin
N
N
F SO H
3
tosylate
HO
H PD
Alimentary
E.Merck
Antithrombotic
Daiichi Seiyaku
Antibiotic
Abbot
Launched
(1990)
CH 3
F
O
EMD-61753
N
N
(Asimadoline)
OH
Ph II
CH 3
O
NH
HN
O
HO
N
HN
2
O
F
ABT-719
Toyama
.
N
H
DX-9065a
Antibiotics
HN
2
CH 3
Ph I(USA)
Ph II(JPN)
O
OH
N
CH 3
Pre Clinical
No
Name
Structure
O
N
(Zyvox)
Maker
Antibacterials
Pharmacia
Antibacterials
Pharmacia
Preclinical
Antibacterials
Pharmacia
Ph I
Diabetes
Eli Lilly
Ph I
Antidepressant
Mistubishi-Tokyo
Ph II
Antidepressant
Yamanouchi
Ph II
O
N
Linezolide
Ther apy
O
F
Stage
Launched
(2000)
NHA c
N
N
O
PNU-172576
N
O
F
NHA c
O
HO
O
O
N
Eperezolide
O
N
N
O
F
NHA c
NHA c
O
OH
NH
SA
- DD
LY-377604
HN
O
H
N
O
NH
O
MKC-242
O
O
HC l
N
H
2
O
O
O
O
O
N
H
YM-992
F
Technology
 Radical reaction
 Chlorination
 Reduction
 Carbohydrates based Chiral Pool
 High pressure reaction(100bar)
 Low temperature reaction(-90oC)
 Classical Resolution
 Enzyme reaction
 Dynamic Kinetic Resolution*
* Under development
World Best
배타적 영업확보
MY
PROCESS
MY
PRODUCT
기술의 고유영역확보
독자적인 신기술
MY
TECHNOLOGY