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

959

O

OSiMe3

CH3

CH3

HN

(Me3 Si)2 NH

N

Saccharin

O

NH

Me3 SiO

N

(170)

= 3H

MeCOO(CH2 )2 OCH2 Br

(80)

H

O

O

HN

CH3

HN

CH3

MeONa / MeOH

O

N

O

N

CH2 OCH2 CH2 OOCMe

CH2 OCH2 CH2 OH

(171)

(169)

B. Double-labelled Compounds

1. Synthesis of

4,4-dimethyl-(3,4-methylenedioxyphenyl)-1-pentene-3-ol

labelled

with 14C and 3H

Carbon-14 has been introduced at the C 1 position of the pentene group of drug 172153,154 starting with Ba14CO3 in 28% yield and tritium has been introduced into the position at C 3 of the chain in the final reaction step by reduction of the ketone group with NaBT4155 (equation 81). The double-labelled compound 172 is applied in pharmacokinetic studies in animals155.

O	Br	Li	14 COOH
	n-BuLi	1. 14 CO2
O		2. H +
			LiA lH4
			THF
	O	14 CHO	14 CH2 OH
	CH3 CC(Me)3 / EtOH / NaOH		(81)
			CrO3 / Py
	O
	14 CH CHCC(Me)3	O	14 CH CHC3HC(Me)3
	NaBT4		OH
		O

(172)

960	Mieczysław Ziełinski´ and Marianna Kanska´

2. Synthesis of 14C- and 3H-labelled 6-nitro-7-sulphamoylbenzo[F ]quinoxalin-2,3- dione (173)

The 14C-labelled 173, effective as a neuroprotectant for cerebral ischemia156, has been synthesized157 from 1,2-diamino-5-sulphamoylnaphthalene 174 and 14C-oxalic acid (equation 82). The tritiated analogue of 173, 173b, has been synthesized as shown in equation 83. 173 shows potent antiparkinsonian effects in primates and rats.

NH2			O
NH2			HN	O
(COOH)2 30 mCi, HCl (aq.)				NH
SO2 NH2	O
(174)		O	HNO3 / H2 SO4
HN

NH

H2 N	SO2	NO2
		(173)
= carbon-14 label
		O
			O	3 H
Br	HN
		NH		3 H2 , PdO / DMF
				SO2 NH2
SONH2				O
				HNO3 / H2 SO4
		3 H	HN	O

NH

H2 N SO2	NO2
(173b)	2.1 mCi,

r.p. > 98% by radio HPLC analysis sp. act. 10 Ci/mmol by HPLC

(82)

(83)

17. Syntheses and uses of isotopically labelled compounds

961

3. Synthesis of carbon-14 and tritium labelled analogues of manoalide

Several analogues of manoalide, isolated159 from Luffariella variabilis, which inhibits phospholipase A2 and possesses topical anti-inflammatory activity159, have been carbon14 and tritium labelled by modification of the non-isotopic syntheses160. Manoalide analogues 4-(1-acetyloxyalkyl)-5-hydroxy-2(5H)-furanones, 175, bearing 14C or 3H in the acetyl molety of the side chain, have been obtained by singlet oxygenation of 2- trialkylsilyl-4-alkylfurans160, 176 (equation 84).

	OAc						OAc
	CH2	2 R •		O2			CH2	2 R
								(84)
R3 1 Si	O				O	O	OH
	(176)						(175)

The substrates 176 have been prepared by Grignard reaction of the carbon-14 labelled alkyl bromides with 2-trialkylsilyl-4-furancarboxaldehyde 177 (equation 85).

							OAc
	CHO						CH2 2 R
				1. Mg
	+	R2	CH2 Br				(85)
R13 Si				2. A c2 O
	O					O	OH
				R3 1 Si
	(177)
R1	= Me or Et	R2 = −(CH2 )6 CH3 , −(CH2 )10 CH3 , −(CH2 )4 Ph

The required carbon-14 labelled alkyl halides have been prepared by standard Grignard reaction-based methods161,162 shown in equations 86a and 86b.

		1. Mg, 2.14 CO2
CH3	(CH2 )nBr	3. BH3 .THF					CH3 (CH2 )14nCH2 Br	(86a)
		4a. HBr (for n = 6)
		4b. TsCl-DMA P, LiBr
			1. HBr
Ph(CH2 )3 CH2 OH			2. Mg,14 CO2			Ph(CH2 )3 CH214 CH2 Br		(86b)
				BH3 .THF
	3.
	4.			HBr

The compound 175a, labelled with carbon-14 in the acetyl moiety, has been obtained as indicated in equation 87 by basic hydrolysis of 4-(1-acetoxytridecyl)-2-trimethylsilylfuran, 178, and reacetylation of the resulting alcohol with acetyl-1-14C-chloride, followed by

962	Mieczysław Ziełinski´ and Marianna Kanska´
singlet oxygenation (equation 87).

	OAc
	(CH2 )11CH3			1. OH−				OOCCH3
				2. Me CCl				(CH2 )11CH3
Me3 Si	O			O
	(178)						•O2
								(87)
			O
		O
						(CH2 )11CH3
	O	O		OH
			(175a)

denotes carbon-14

Tritium in the acetyl moiety 175b has been obtained using, in a similar sequence of reactions, dibromoacetic acid and subsequent catalytic halogen tritium exchange (equation 88).

OAc

(CH2 )11CH3 1. OH−

2. CHBr2 COCl

O

O CHBr2

Et3 Si	O						(CH2 )11CH3
				O	1. 3	H2 , Pd/C	•O2	(88)
						2.
			O
					CH3
				(CH2 )11CH3
	O	O	OH
			(175b)
	H denotes tritium

The 14C- and 3H-labelled compounds 175 are used in biological studies.

17. Syntheses and uses of isotopically labelled compounds

963

4. Synthesis of [ 14C]- and [ 3H]-labelled (C)-f1R-[1˛,2˛(Z ) 3ˇ,4˛]g-7-f3-[(phenylsul- phonyl)amino]bicyclo[2.2.1]hept-2-ylg-5-heptenoic acid ((C)-S -145, 179) and its Ca salt (S -1452, 180)

S-145, 179 thromboxane A2 (TXA2)-receptor antagonist which efficiently suppresses platelet aggregation and vascular, respiratory smooth muscle constriction163,164, and its chemically stable calcium salt, 180, have been labelled with 3H and 14C for metabolic studies and for characterization of the receptor binding165 as well as for use in the chemotherapy of various TXA2- and PGH2-mediated circulatory disorders like angina pectoris, asthma and myocardial infraction.

	COOH
NHSO2	3 H
[3 H]-(+)- S-145	(179)
		COO−
		Ca2 + • 2H2 O
	NHSO2

[14 C]- S-1452 (180)

= [U-14 C]benzene

The amine 181 reacting with solution of [4-3H]benzenesulphonyl chloride in benzene gave the methyl ester 182, which after treatment with sodium hydroxide in MeOH and chromatography provided the sodium salt of 179 (equation 89). 180 have been prepared similarly using [U-14C]benzenesulphonyl chloride synthesized from [U-14C]benzene (equation 90).

COOMe

	8 steps	COOMe
COOH	NH2	(181)
	Et3 N, DMAP, RT, 4 h
	work-up		(89)
	3 H	SO2 Cl
	COOMe
	1N NaOH / MeOH, RT, 15 h
		179
NHSO2	3 H	chromatography

(182)

964	Mieczysław Ziełinski´ and Marianna Kanska´
					SO3 H					SO2 Cl
		H2 SO4						SOCl2

181, Et3 N, DMAP

		COOMe
		(90)
	NHSO2
	1 N NaOH
		COONa
		1. CaCl2
NHSO2		180
		2. separations

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

CN GROUPS LABELLED WITH RADIOACTIVE CARBON

A. Compounds Labelled with Carbon-11

1. New synthesis of 11C-labelled phosgene

[11C]Phosgene, allowing the insertion of 11C-labelled carbonyl function between two stereochemically close amino functions, has been usually synthesized from [11CO2] either by photochemical reaction166 or by reaction on platinum chloride167 (equation 91). To obtain [11C]phosgene for receptor studies by PET, [11C]methane has been chosen as the precursor168, using chlorination of [11C]CH4 to carbon tetrachloride followed by catalytic oxidation to [11C]phosgene (equation 92).

11COCl2

O2

Cl2 , U.V.

sp. act. 100 mCi/ mol

N(p, α)11 C

11CO2

Zn

11CO

(91)

400 ° C

380 ° C

PtCl4

11COCl2

14

N p, ˛

11

C !

11

CH4

pumice-stone-CuCl2

11

iron fillings catalyst

11

COCl2

92

!

CCl4 !

17. Syntheses and uses of isotopically labelled compounds

965

2. Synthesis of 9-[ 11C]heptadecan-9-one (183)

183 has been synthesized169 from di-n-octylthexylborane with K11CN followed by rearrangement and alkaline oxidation (equation 93). During rearrangement using TFAA the octyl groups migrated from the boron to carbon atom. Equation 93 is applicable to the synthesis of various 11C-labelled dialkyl ketones, e.g. of 10-[11C]nonadecan-10-one with di-n-nonylthexyl borane169. Synthesis of 11C-labelled hexestrone, 17ˇ-estradiol and related hormones with the use of organoboranes are under investigation169,170.

2{CH3 (CH2 )5C CH2 } + Me2 C CMe2 + BH3 .THF THF [CH3 (CH2 )7 ]2 BCMe2 CHMe2

					1. (CF3 )2 O, ice bath, RT, 5 min stir.		CN−
						CN	(93)
					2. 3M NaOH / 50% H2 O2 , 0 °C
						(n-C8 H1 7 )2 B
(n-C8 H1 7 )2 C			O
					3. Seperations, HPLC
	95% r. purity					CMe2 CHMe2
(183)
	1 1 C
C =

3. Synthesis of high specific activity [11C]urea

[11C]urea, used in production of NCA radiopharmaceuticals, has been produced171 from NCA 11CN 172 by quantitative oxidation of the 11CN to O 11CN with KMnO4 at

pH D 13.5, decomposing the excess of KMnO4 with H2O2 and decomposition of KO11CN to NH4O11CN followed by thermal transformation of NH4O11CN in ethanol medium into [11C]urea (equation 94). The oxidation of CN into OCN is also quantitative in the presence of copper hydroxide173 as a catalyst (equation 95), but its use presents several disadvantages171 and additional purification of the 11C-labelled compound is required. The conversion of NH4O11CN to [11C]urea is pseudo-first-order in the presence of the excess of ammonium ions and has been studied173 175.

11CN	KMnO4, aqueous KOH, H2O2	(NH4)2SO4, EtOH	11CO
	! O11CN ! NH2 2			94
	Cu(OH)2
3K11CN C 2KMnO4 C H2O ! 3KO11CN C 2MnO2 C 2KOH				95

4. Synthesis of [2-11C]5,5-dimethyl-2,4-oxazolidinedione (184)

[2-11C]DMO, 184, is used to measure routinely regional cerebral tissue pH in vivo in man by PET, and is helpful in establishing treatment regimens for patients with primary and/or metastatic brain tumors and their focal pathology176. It has been synthesized177 utilizing [11C]phosgene178, DMC and HIBA as shown in equations 96a and 96b). The amount injected into a human is no more than 1 mg of DMO, far below the value 900 mg stated in the protocols179.

5. Synthesis of 2-[ 11C]-5,5-diphenylhydantoin (185)

DPH, 185, widely used in treatment of epileptic seizures180, has been labelled with 11C and isolated in high specific activity in reaction of [11C]urea with benzil181 (equation 97). The effect of reaction time, of reaction temperature and of KOH molarity on the yield

966	Mieczysław Ziełinski´ and Marianna Kanska´

of [11C]DPH has been investigated to optimize the reaction conditions. The effect of various reactant concentrations (ammonium sulphate, hydrogen peroxide) has also been studied. The instability of 185 under the experimental conditions has been assigned to its dissociation to diphenylhydantoic acid (DPHA), which decomposes in turn to ˛,˛- diphenylglycine (DPG) and carbonate (equation 98).

2MeONa

+ Cl2 11C

O

anhyd. MeOH

(MeO)2

11C

O

(96a)

O

HN

O

1. MeONa, anhyd. MeOH, 100 − 150 °C, 5 − 20 min

+ (MeO)2 11C

O

11

2. Work-up, purifications by HPLC and FC

OH

NH2

C

O

O

HIBA

DMC

(184) DMO

HIBA = 2-hydroxyisobutyramide

DMC = dimethylcarbonate

(96b)

Ph

Ph

O

Ph

OH

NH

Ph

KOH

+ (NH2 )2 11C

O

KOH

11C

Ph

heat

heat

NH

O

O

Ph

O

O

OH

benzil

benzilic acid

(185) DPH

(97)

O

Ph

11C

NH2

Ph

NH2

H2 O / KOH

Ph

NH

H2 O / KOH

Ph

+

11 CO

2

− + NH

+

185

heat

heat

O

OH

O

OH

DPHA

DPG

(98)

6. Routine production of [ 11C]-1-aminocyclopentanecarboxylic acid (186)

([11C]-ACPC), 186, used to study the metabolism of tumors by PET, has been synthesized routinely182 as shown in equation 99, for medical use, and since 1982 in yield higher than reported previously183,184. Optimal conditions for H11CN production have been established182. The product 186 has been suitable for injection.

7. Automated radiosynthesis of NCA-S-[ 11C]CGP 12177 (187)

S-(30-t-Butylamino-20-hydoxypropoxy)-benzoimidazol-2-[11C]one, 187, has been synthesized185 in >95% S-( )-enantiomeric excess (after HPLC) in three steps from 2,3-dinitrophenol and the chiral auxiliary, S-glycidyl-3-nitrobenzenesulphonate, to provide the precursor 188 for the amine 189 and asymmetrical diamine, 190, which in reaction with [11C]phosgene186 gave 187 (equation 100). The S-enantiomer of [11C]CPG, 187 is being applied to study ˇ-receptors in heart and in lung with PET and in biological experiments186, since previous studies with S-, R- and R,S-[3H]CPG 12177 showed

17. Syntheses and uses of isotopically labelled compounds

967

that the S-enantiomer has greater affinity than the R-enantiomer for ˇ-adrenergic receptors187,188.

							O
							11C	NH
O			H 11CN, KCN
	(NH4 )2 CO3 , NH4 Cl, 185 °C						HN
									(99)
								O
			185 °C
			11COOH		NaOH
			NH2
(186) 60 ± 3% yield
OH								NO2	NO2
NO2
		O	CHCH2 OSO2	C6 H4 NO2		-p
							O	CHCH2 O
NO2			NaH / DMF under N2
(191)									(188)
			NO2		NO2		reflux
								t-BuNH2
t-BuNHCH2
HO CCH2			O
	H
			(189)
			H2 , Pd, RT					NH2	NH2
	Pd / C in EtOH				t-BuNHCH2
					HO CCH2 O
							H
t-BuNHCH2							(190) 24% from 191
			1. CH2 Cl2 / toluene, 5 min
HO
			2. 95−125 °C, 2 min
	O		3. HPLC micropore filtration
H						11		/ O2
						COCl2
			NH
			11 C O
			NH
(187) 3.7−5.9 GBq ready for clinical use									(100)

968 Mieczysław Ziełinski´ and Marianna Kanska´

8. Synthesis of 11C-labelled ˛,ˇ-unsaturated nitriles

The synthetically useful ˛,ˇ-unsaturated [11C]-labelled precursors, [11C]acrylonitrile (192) and [11C]cinnamonitrile (193), have been prepared189 191 with potassium [11C]cyanide (equation 101). The substitution reactions have been performed in MeCN, benzene, 1,2-dichlorobenzene, DMSO and THF solvents, but the highest radiochemical yields were obtained in acetonitrile. 192 was used in a model reaction (equation 102) to synthesize 2-cyano[11C]ethyldimethyl malonate 194 from sodium hydride/dimethyl malonate.

RHC CHBr		K[11C]N			Pd0 [P(Ph)3]4, 18-crown-6, acetonitrile				RHC	CH11CN	101
D	C			!					D
				40 °C (compd. 192) or 100			°C (compd. 193)		(192)	R D H
COOMe									(193)	R D Ph
								MeOOC
		+ CH2			CH11CN	NaH / DMSO				11 CN	(102)
						80 °C, 3 min

COOMe	MeOOC
	(194)

9. Synthesis of [11C]propenoic acid, [1-11C]propenoyl chloride and N-[11C]- substituted propenamides

[11C]Acrylic acid has been obtained191 by 11C carbonation of ethenylmagnesium bromide in THF and separation of the [11C]propenoic acid on reverse-phase column.

[1-11C]acryloyl chloride and [1-11C]propenamides have	been	prepared as outlined
in equation 103. Besides N-propyl[11C]propenamide,	195,	N-phenylpropenamide,

196, 1-piperidylpropenone, 197 and 1-(1,2,3,4-tetrahydroisoquinolin-3-yl)-propenone, 198, the Michael adducts 1,3-bis-piperidylpropanone (199) and 1,3-bis(1,2,3,4- tetrahydroisoquinolin-3-yl)propanone (200) have been prepared also191.

CH2

CH11 COOH

H3 O+

o-C6 H4 (COCl)2

O

CH2

CH11 COOMgBr

11C

CH2

CH

2,6-di-t-But Pyridine

8 min, T below 40 °C

Cl

R1R2 NH

O

O

3 R 4 RNH, CCl4

solvent

CH2 CH 11C

(103)

R3 R4 NCH2

CH2

11CNR1R2

80 °C, 2−3 h

(195) R1 = Pr, R2 = H

(199) R1 R2 = R3 R4 =

(CH2 )5

NR1R2

(196) R1 = Ph, R2 = H

(CH2 )2

(197) R1R2 =

(CH2 )5

(200) R1 R2 = R3 R4 =

(CH2 )2

CH2

(198) R1R2 =

CH2