Patai S., Rappoport Z. 1997 The chemistry of functional groups. The chemistry of double-bonded functional groups / 0909 110

17. Syntheses and uses of isotopically labelled compounds

989

16.1 š 2.9 h. 66.8 93.2% of radioactive dose was recovered in urine and 5.8 7.0% in feces over 13 days after dosing. The drug was extensively metabolized by structural alterations at the phenyl ring, pyrrol ring and the nitrile group.

HOCH2 O

OH

HO

anh. NH3 flow

H2 SO4

OH

BaCO3

BaNCN

H2 NCN

D(-)arabinose, 60 °C, 2 h

NH4 OH/H2 O/MeOH

O

HOCH2

O

N

HC

CCOOMe

O

THF / EtOH, 90 °C, 5h

N

OH

HOCH2

O

O

MeCOBr

O

DMF, reflux, 1.75 h

OH

(264)

HN

O

N

1. Bu3 SnH/ THF, reflux

AcOCH2 O

2. ICl / CH2 Cl2 / reflux

3. Me3 SiC

CH, (Ph3 P)2 PdCl

AcO

Br

O

(267)

O

R

HN

HN

1. NaOMe / MeOH

O

N

O

N

AcOCH2 O

2. Pd / C / H2

HOCH2

O

HO

AcO

(265a) R = H

(266a)

R =

C

CH

(265b) R = I

(266b)

R =

CH2 CH3

(266c) R =

C

CSiMe3

NH2

N

(149)

R

990

O N

I

I

Mieczysław Ziełinski´ and Marianna Kanska´

O
	CONHC(Me)3

H		O	NH
(268)				(269)
		I				CN
		Cl	Cl		Cl		Cl
ClSO3 H, SO2	Cl2			CuCN, MeCN
				Pyridine
		Cl	Cl		Cl		Cl
		I				CN
				MeCN, DMSO (cat.)			KF, DMF

	CF3	O	F		CN
		O	F	F	F
	Cl			6 steps
		F	Me	F	F
			F		CN
		(270)			(150)

		CN
		NH
N

Me O O

R

(271)R = H

(272)R = OH

17. Syntheses and uses of isotopically labelled compounds

991

19. Synthesis of 14C-labelled BW A871 (273)

273 has been synthesized and 14C-labelled for topical treatment286 of Trichomonas vaginalis and Candida albicans. The 14C label has been introduced into the 3 position of the isoquinoline ring by treating the 3-propyloxybenzyl chloride with K14CN, followed by reduction of the nitrile to the amine which, treated with cyclohexyl acryloyl chloride, gave the amide. Cyclization of the amide provided 273.

n-PrO

N

(273)

20. Synthesis of 14C-labelled DTIC (274)

274, an anti-tumor drug287, has been synthesized288 from 275 with di[14C]methylamine (equation 151).

	O					O
N		NH2			N	NH2
			HNO2
					−	+
NH	NH2 .ΗCΙ				NH	N2
					(275)
		O	Sp. act 2.15 GBq/mmol			(151)
N			NH2		Me2 NH
	NH	N
			CH3

CH3

(274)DTIC

70.9% radiochemical yield

21. Synthesis of 14C- and 3H-labelled ICI-176,334 (276)

276, intended for use in the clinical treatment particularly of cancer of the prostate, has been uniformly 14C-labelled in the 4-flourophenyl group289 and in the cyano group. Thus 276a and 276b have been obtained from potassium [14C]cyanide in multi-stage processes,

992	Mieczysław Ziełinski´ and Marianna Kanska´

while 277a has been prepared by catalytic dehalogenation of the corresponding brominated precursor, 277b.

				CF3
		O	HO
			NH	CN
F		S
		O	O
(276a) labelled in ring
				CF3
(276b) labelled in CN group
		O	HO	CN
			NH
F		S

O O

R

(277a) R = 3 H, sp. act 13.8 Ci/mmol, r.purity 98%

(277b) R = Br

(S)
O	NH
OH
		HOOC	Me
	*	NH	N	(S)
NH		(CH2 )4 (S) NH	(S)
	O	(278)	O	COOH
				(S)

(S)N

O

O O

N R

SO2 Ph

(279)

17. Syntheses and uses of isotopically labelled compounds

993

22. Synthesis of 14C-labelled BW B385C (278)

The antihypertensive agent 278 has been 14C-labelled by carbonation of the 2-lithiated indole, 279 (R D Li), with 14CO2 and subsequent combination with a preformed peptide side chain. In 279 (R D H) the indole nitrogen has been converted into its benzenesulphonyl derivative to direct properly the lithiation while the 2-hydroxy-3- isopropylaminopropoxy side chain has been protected as oxazolidin-2-one290.

23. Synthesis of [14C]BRL 26830A (280)

280, a novel ˇ-adrenoceptor agonist291 which may find clinical utility in the treatment of both obesity and type II diabetes291, has been synthesized292 from K14CN in 9 steps (equation 152).

p-B rC6 H4 COOMe

CuSO4 1. Na2 S2 O5; 2.KCN

CuCN

p-NCC6 H4 COOMe

Ni/A l/HCOOH

O2 N

CH3 CH2

NO2

Fe,HCl,MeOH

Me

C

CHC6 H4 COOMe-p

p-OHCC6 H4 COOMe

Me

HO

PhCH(OH)CH2 NH2

MeCCH2 C6 H4 COOMe-p

Ph

CHCH2 N

CCH2

C6 H4 COOMe-p

O

Me

NaBH4

HO

−C6 H4 COOMe-p

CHCH2 NHCHCH2

(152)

Ph

Fumaric acid

HO

COOH

NH

HOOC

COOMe

(280)[14 C]BRL 26830A

24. Synthesis of 1-benzyl-4-f(5,6-dimethoxy[2-14C]-1-indanon)-2-ylg-methylpiperi- dine hydrochloride, E2020-14C (281)

281, one of the most potent AChE (acetylcholineesterase inhibitors293), a candidate for drug treatment of patients with Alzheimer’s disease, has been synthesized294 using

994	Mieczysław Ziełinski´ and Marianna Kanska´

5,6-dimethoxy[2-14C]-1-indanone, 282, as the starting labelled material (equation 153). 282 has been prepared as shown in equation 154. [14C]-281 is applied for pharmacokinetic profile studies.

O

MeO
		+ OHC	NCH2 Ph
MeO
	(282)
			O
		MeO
				CH	NCH2 Ph (153)
		MeO
		1. H2 /THF/10% pd/C
		O		2. HCl/A cOEt
MeO
			NCH2 Ph.HCI
MeO
		[14 C]-(281)
MeO				MeO
	+		1. base		COOH
		CH2 (COOEt)2	2. acid
MeO	CHO			MeO
			H2		(154)
					O
	MeO			MeO
		COOH	1. SOCl2
			2. A lCl3
	MeO			MeO
				(282)

25. Synthesis of 14C-labelled tetrahydroacridine (283)

The 9-amino-8-fluoro-2,4-methano-1,2,3,4-tetrahydro[9-14C]acridine citrate, SM-10888, 283, has been synthesized295 in five steps (equation 155) for cholinergic treatment in Alzheimer disease296 300.

26. Synthesis of 14C-labelled Cefclidin (286)

286, a new injectable cephalosporin with potent antipseudomonal activity301,302, has been prepared303 from 287, as shown in equations 156 and 157.

	17. Syntheses and uses of isotopically labelled compounds							995
		COOH			CONH2			CN
	F	F		F	F	F		F
	284
BaCO3

(155)

F

NH2

COOH

CN

F

NH2

.

COOH .

285

2

HO

nH2 O

3

N

COOH

(283)

Li

F

F

O

(284)

(285)

= carbon-14 label

CONH2

borane−dimethy sulphide complex

NH

BrCH2 COOH

BrCH2 CH2 OH

K2 CO3 , KI, i-PrOH

CN

CONH2

1. LDA /THF

1. SOCl2 ; 2. MeCN

(156)

2. TsOH.H2 O

N

N

CI

OH

N

CN

1. conc.H2 SO4 ; 2. NH3

N

CONH2

LDA = (i-Pr)2 NLiTHF

(287)

996		Mieczysław Ziełinski´ and Marianna Kanska´
		O
			NH		S
						1. NaI
H2 N	N	N		N	CH2 Cl	2. 287
	S	OMe	O			3. TFA −anisole
TFA = CF3 COOH, PMB = p-methyloxybenzyl					COOPMB
						(157)
		O
			NH		S
					+N
H2 N	N	N		N		CONH2
	S	OMe	O

COO−

(286)

27. Synthesis of [Ph-UL-14C]ractopamine hydrochloride (288)

(EL-737), 288, promoting growth and carcass leanness when fed to swine304, has been uniformly labelled305 with carbon-14 in one of the two phenyl rings in six-step synthesis in 14% yield (equation 158).

HO		CHO + CH3 COCH3	NaOH	HO
					O
					NaHTe / abs EtOH
				30 min reflux under N2
	NH2	BH3 .THF			CH3 ONH2 / MeOH	O

N OMe

O

1. p-HOC6 H4 CCH2 Br, NaHCO3 / EtOA c; 2. HCl

OH

(158)

N

		H O
	HO	.
		HCl

H2 , 5% Pd/C/MeOH

OH

N

HO	H OH
	.
	HCl

(288)

17. Syntheses and uses of isotopically labelled compounds

997

28. Synthesis of carbon-14 labelled LTD4 antagonist MK-571 (289)

The title compound, [14C]MK-571, 289, a promising antiasthmatic agent306,307, has been synthesized308 from Na14CN via the sequence shown in equation 159.

			OHC
OCH	Br	NaCN		CN
				.	CuBr
		CuCN
		DMF
		2. aq. NaCN, EtOA c 1.
			Cl	N	Me
				A c2 O , xylene
	Cl		N	CN
	NaH2 PO2 ,Py
	Raney Ni				COOMe
				S
		1. HS(CH2 )2	CONMe2 ,		CONMe2
	CHO
		(Me3 Si)2 NH, lmidazole,			S

2.HS(CH2 )2 COOMe

.BF3 -Et2 O, −30 °C

2. H+

	1. LiOH, THF/H2 O
	S	COOMe
Cl		CONMe2
	N	S
	[M C] MK-571 (289),
	stored protected
	from light at
	−55°C	(159)

V. SYNTHESES AND USES OF COMPOUNDS CONTAINING C=C, C=O OR CN

GROUPS LABELLED WITH RADIOACTIVE HALOGEN

A. Compounds Labelled with Fluorine-18

1. Synthesis of [18F]flunarizine (290)

290, a clinically used calcium channel blocker of the piperazine class309 recently used for treatment of neurological disorders such as epilepsy and migrene309, has been prepared

998	Mieczysław Ziełinski´ and Marianna Kanska´

(equation 160) for in vivo biodistribution studies310.

p-FC6 H4 CH(Cl)C6 H4 18 F -p + HN

N

Ph

DMSO, K2 CO3

F

N

N

(160)

18 F

(290)

2. Synthesis of [18F](3-N-methyl)benperidol (NMB, 291)

291 has been synthesized as shown in equation 161311.

		O		O
			18F − /TBA H/ DMSO / MW 312
	O2 N	O		18 F
	Me			HCl / MeOH
	N	N	NH
				O
			, anh. KI,
	1-methyl-2-pyrrolidinone solvent			(CH2 )3 Cl	(161)
			18 F	O	Me
				N
				N
			O
				N
		18 F	TBAH = (n - But)4 NOH	(291) [18F]NMB