IODOTYROSINE DERIVATIVES AND PROCESS FOR PREPARING IODOTYROSINE DERIVATIVES
20240067599 · 2024-02-29
Assignee
Inventors
- Alexander Hoepping (Radeberg, DE)
- Christoph MEYER (Radeberg, DE)
- Desna JOSEPH (Radeberg, DE)
- Stefan David KÖSTER (Radeberg, DE)
- Erik EISELT (Radeberg, DE)
Cpc classification
C07C229/36
CHEMISTRY; METALLURGY
International classification
Abstract
A compound of general formula I
##STR00001##
wherein A is selected from the group of an unbranched or branched alky group with 1 to 12 carbon atoms, an R.sup.1OR.sup.2 group, an R.sup.1Si(R.sup.3R.sup.4R.sup.5) group, an R.sup.1OSi(R.sup.3R.sup.4R.sup.5) group, a C(O)OR.sup.9Si(R.sup.3R.sup.4R.sup.5) group, a CH(OR.sup.6)(OR.sup.7) group, an R.sup.1CH(OR.sup.6)(OR.sup.7) group, or an R.sup.1OC(O)OR.sup.8 group; SG is a protective group; R.sup.1 is a divalent hydrocarbon residue with 1 to 12 carbon atoms; R.sup.2 is a monovalent hydrocarbon residue with 1 to 12 carbon atoms; R.sup.3, R.sup.4 and R.sup.5 each independently are a monovalent hydrocarbon residue with 1 to 12 carbon atoms; R.sup.6 and R.sup.7 each independently are a monovalent hydrocarbon residue with 1 to 12 carbon atoms; R.sup.8 is a monovalent hydrocarbon residue with 1 to 12 carbon atoms; and R.sup.9 is a divalent hydrocarbon residue with 1 to 12 carbon atoms.
Claims
1-15. (canceled)
16. A compound of general formula I ##STR00042## wherein A is selected from the group consisting of an unbranched or branched alkyl group with 1 to 12 carbon atoms, an R.sup.1OR.sup.2 group, an R.sup.1Si(R.sup.3R.sup.4R.sup.5) group, an R.sup.1OSi(R.sup.3R.sup.4R.sup.5) group, a C(O)OR.sup.9Si(R.sup.3R.sup.4R.sup.5) group, a CH(OR.sup.6)(OR.sup.7) group, an R.sup.1CH(OR.sup.6)(OR.sup.7) group, an R.sup.1OC(O)OR.sup.8 group; SG is a protective group; R.sup.1 is a divalent hydrocarbon residue with 1 to 12 carbon atoms; R.sup.2 is a monovalent hydrocarbon residue with 1 to 12 carbon atoms; R.sup.3, R.sup.4 and R.sup.5 each independently are a monovalent hydrocarbon residue with 1 to 12 carbon atoms; R.sup.6 and R.sup.7 each independently are a monovalent hydrocarbon residue with 1 to 12 carbon atoms; R.sup.8 is a monovalent hydrocarbon residue with 1 to 12 carbon atoms; and R.sup.9 is a divalent hydrocarbon residue with 1 to 12 carbon atoms.
17. The compound according to claim 16, wherein the compound is a compound of general formula I-A ##STR00043## wherein A and SG have the meanings as previously defined.
18. The compound according to claim 16, wherein SG is selected from the group consisting of a fluorenylmethylenoxycarbonyl group (Fmoc), a tert-butoxycarbonyl group (boc), and a benzyloxycarbonyl group.
19. The compound according to claim 16, wherein A is selected from the group consisting of an unbranched or branched alkyl group with 1 to 12 carbon atoms, an R.sup.1OR.sup.2 group, an R.sup.1Si(R.sup.3R.sup.4R.sup.5) group, and a C(O)OR.sup.9Si(R.sup.3R.sup.4R.sup.5) group, wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, and R.sup.9 have the meanings as previously defined.
20. The compound according to claim 16, wherein A is selected from the group consisting of an alkyl group with 1 to 6 carbon atoms; an R.sup.1OR.sup.2 group in which R.sup.1 is an alkylene group with 1 to 6 carbon atoms and R.sup.2 is an unbranched or branched alkyl group with 1 to 6 carbon atoms; an R.sup.1Si(R.sup.3R.sup.4R.sup.5) group in which R.sup.1 is an alkylene group with 1 to 6 carbon atoms and R.sup.3, R.sup.4 and R.sup.5 each independently are an unbranched or branched alkyl group with 1 to 6 carbon atoms or an aryl group; and a C(O)OR.sup.9Si(R.sup.3R.sup.4R.sup.5) group in which R.sup.9 is an alkylene group with 1 to 6 carbon atoms and R.sup.3, R.sup.4 and R.sup.5 each independently are an unbranched or branched alkyl group with 1 to 6 carbon atoms or an aryl group.
21. The compound according to claim 16, wherein A is selected from the group consisting of an alkyl group with 1 to 6 carbon atoms; an R.sup.1OR.sup.2 group in which R.sup.1 is an alkylene group with 1 to 4 carbon atoms and R.sup.2 is an unbranched or branched alkyl group with 1 to 6 carbon atoms; an R.sup.1Si(R.sup.3R.sup.4R.sup.5) group in which R.sup.1 is an alkylene group with 1 to 4 carbon atoms and R.sup.3, R.sup.4 and R.sup.5 each independently are an unbranched or branched alkyl group with 1 to 6 carbon atoms or an aryl group; and a C(O)OR.sup.9Si(R.sup.3R.sup.4R.sup.5) group in which R.sup.9 is an alkylene group with 1 to 6 carbon atoms and R.sup.3, R.sup.4 and R.sup.5 each independently are an unbranched or branched alkyl group with 1 to 6 carbon atoms or an aryl group.
22. The compound according to claim 16, wherein the compound is 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(3-iodo-4-(methoxymethoxy)phenyl)propionic acid, 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(3-iodo-4-(((2-(trimethylsilyl)ethoxy)carbonyl)oxy)phenyl)propionic acid, 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(4-(2-(tert-butyldiphenylsilyl)ethoxy)-3-iodophenyl)propionic acid, or 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(4-(tert-butoxy)-3-iodophenyl)propionic acid.
23. The compound according to claim 16, wherein the compound is 2-((tert-butoxycarbonyl)amino)-3-(3-iodo-4-(methoxymethoxy)phenyl)propionic acid, 2-((tert-butoxycarbonyl)amino)-3-(3-iodo-4-(((2-(trimethylsilyl)ethoxy)carbonyl)oxy)phenyl)propionic acid, 2-((tert-butoxycarbonyl)amino)-3-(4-(2-(tert-butyldiphenylsilyl)ethoxy)-3-iodophenyl)propionic acid, or 2-((tert-butoxyc arbonyl) amino)-3-(4-(tert-butoxy)-3-iodophenyl)propionic acid.
24. A method for the preparation of the compound according to claiml6, comprising reacting a compound of general formula II ##STR00044## wherein SG is a protective group, with a compound of general formula X-A, wherein X is halogen or ammonium and A is selected from the group consisting of an unbranched or branched alkyl group with 1 to 12 carbon atoms, an R.sup.1OR.sup.2 group, an R.sup.1Si(R.sup.3R.sup.4R.sup.5) group, an R.sup.1OSi(R.sup.3R.sup.4R.sup.5) group, a C(O)OR.sup.9Si(R.sup.3R.sup.4R.sup.5) group, a CH(OR.sup.6)(OR.sup.7) group, an R.sup.1CH(OR.sup.6)(OR.sup.7) group, an R.sup.1OC(O)OR.sup.8 group; R.sup.1 is a divalent hydrocarbon residue with 1 to 12 carbon atoms; R.sup.2 is a monovalent hydrocarbon residue with 1 to 12 carbon atoms; R.sup.3, R.sup.4 and R.sup.5 each independently are a monovalent hydrocarbon residue with 1 to 12 carbon atoms; R.sup.6 and R.sup.7 each independently are a monovalent hydrocarbon residue with 1 to 12 carbon atoms; R.sup.8 is a monovalent hydrocarbon residue with 1 to 12 carbon atoms; and R.sup.9 is a divalent hydrocarbon residue with 1 to 12 carbon atoms, to form a compound of general formula I ##STR00045## wherein A and SG have the meanings given in connection with formula II.
25. The method according to claim 24, wherein the compound of general formula II is reacted with a compound of general formula X-A to obtain a compound of general formula III ##STR00046## and subsequently the compound of general formula III is reacted to form a compound of general formula I.
26. The method according to claim 24, wherein the compound of general formula II is prepared from a compound of general formula IV ##STR00047## by introducing a protective group SG at the amino group of the compound of general formula IV.
27. A method for preparing a peptide, comprising reacting a compound according to claim 16.
28. The method according to claim 27, wherein the peptide is a compound of general formula IX ##STR00048## wherein R.sup.10 is hydrogen or one or more amino acid entities; and R.sup.11 is hydrogen or one or more amino acid entities, with the proviso that, if R.sup.10 is hydrogen R.sup.11 is not hydrogen and that if R.sup.11 is hydrogen R.sup.10 is not hydrogen.
29. The method according to claim 27, wherein a compound of general formula VIII ##STR00049## wherein A is selected from the group consisting of an unbranched or branched alkyl group with 1 to 12 carbon atoms, an R.sup.1OR.sup.2 group, an R.sup.1Si(R.sup.3R.sup.4R.sup.5) group, an R.sup.1OSi(R.sup.3R.sup.4R.sup.5) group, a C(O)OR.sup.9Si(R.sup.3R.sup.4R.sup.5) group, a CH(OR.sup.6)(OR.sup.7) group, an R.sup.1CH(OR.sup.6)(OR.sup.7) group, an R.sup.1OC(O)OR.sup.8 group; R.sup.1 is a divalent hydrocarbon residue with 1 to 12 carbon atoms; R.sup.2 is a monovalent hydrocarbon residue with 1 to 12 carbon atoms; R.sup.3, R.sup.4 and R.sup.5 each independently are a monovalent hydrocarbon residue with 1 to 12 carbon atoms; R.sup.6 and R.sup.7 each independently are a monovalent hydrocarbon residue with 1 to 12 carbon atoms; R.sup.8 is a monovalent hydrocarbon residue with 1 to 12 carbon atoms; R.sup.9 is a divalent hydrocarbon residue with 1 to 12 carbon atoms; and R.sup.10 and R.sup.11 have the meanings given in connection with the compound of general formula IX; is reacted to a compound of general formula IX.
30. The method according to claim 28, wherein the reaction is carried out in the acidic range.
Description
DETAILED DESCRIPTION
[0078] In the following, the invention is explained in more detail with the help of examples which are not intended to limit the invention.
[0079] Examples of inventive compounds are given in table 1. The compounds 1D, 2D, 3D, and 4D possess am R configuration and are derivatives of D-tyrosine. The compounds 1L, 2L, 3L, and 4L possess an S configuration and are derivatives of L-tyrosine.
TABLE-US-00001 TABLE 1 Name Compound Structure (abbr. chem. name) 1D
[0080] The compounds mentioned in table 1 are exemplary compounds of general formula I and of general formula Ia. The compounds 1D and 1L are compounds of general formula Ia in which A is an R.sup.1OR.sup.2 group in which R.sup.1 is a methylene group and R.sup.2 is a methyl group. The compounds 2D and 2L are compounds of general formula Ia in which A is an R.sup.1Si(R.sup.3R.sup.4R.sup.5) group in which R.sup.1 is CH.sub.2CH.sub.2 and R.sup.3, R.sup.4 and R.sup.5 each are a methyl group. The compounds 3D and 3L are compounds of general formula Ia in which A is an R.sup.1Si(R.sup.3R.sup.4R.sup.5) group in which R.sup.1 is CH.sub.2CH.sub.2CH.sub.2, R.sup.3 and R.sup.4 each are a phenyl group and R.sup.5 is a tert-butyl group. The compounds 4D and 4L are compounds of general formula Ia in which A is a tert-butyl group.
[0081] Further examples of inventive compounds are given in table 1 a. The compounds 5D, 6D, 7D and 8D possess an R configuration and are derivatives of D-tyrosine. The compounds 5L, 6L, 7L and 8L possess an S configuration and are derivatives of L-tyrosine.
TABLE-US-00002 TABLE 1a Name Compound Structure (abbr. chem. name) 5D
[0082] The compounds mentioned in table 1a are exemplary compounds of general formula I and of general formula Ib. The compounds 5D and 5L are compounds of general formula Ib in which A is an R.sup.1OR.sup.2 group in which R.sup.1 is a methylene group and R.sup.2 is a methyl group. The compounds 6D and 6L are compounds of general formula Ib in which A is an R.sup.1Si(R.sup.3R.sup.4R.sup.5) group in which R.sup.1 is CH.sub.2CH.sub.2 and R.sup.3, R.sup.4 and R.sup.5 each are a methyl group. The compounds 7D and 7L are compounds of general formula Ib in which A is an R.sup.1Si(R.sup.3R.sup.4R.sup.5) group in which R.sup.1 is CH.sub.2CH.sub.2CH.sub.2, R.sup.3 and R.sup.4 each are a phenyl group and R.sup.5 is a tert-butyl group. The compounds 8D and 8L are compounds of general formula Ib in which A is a tert-butyl group.
[0083] The abbreviations used in the abbreviated chemical names have the following meaning: [0084] Boc tert-butoxy carbonyl [0085] Fmoc 9-fluorenylmethyloxycarbonyl [0086] MOM methoxymethyl [0087] OH hydroxy group of the carboxyl entity [0088] TBDPSE tert-butyldiphenylsilylethyl [0089] TEOC 2-(trimethylsilyl)ethoxycarbonyl [0090] D-Tyr D-tyrosine [0091] L-Tyr L-tyrosine
EXAMPLE 1
Synthesis of Fmoc-3-iodo-D-Tyr(MOM)-OH (1D)
[0092] The synthesis of Fmoc-3-iodo-D-Tyr(MOM)-OH was carried out as described in scheme B1:
##STR00036##
In step (a) (R)-2-amino-3-(4-hydroxy-3-iodophenyl)propionic acid 11 (also referred to as 3-iodo-D-tyrosine or 3-iodo-D-Tyr-OH) is reacted with N-(9-fluorenylmethoxycarbonyloxy)-succinimide (Fmoc-OSu) to obtain (R)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(4-hydroxy-3-iodophenyl)propionic acid 12 (also referred to as Fmoc-3-iodo-D-Tyr-OH). The reaction takes place in mixture of an aqueous sodium carbonate solution and 1,4-dioxane. Then, in step (b) compound 12 is reacted with methoxymethylbromide (CH.sub.3OCH.sub.2Br) to methoxymethyl-(R)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(3-iodo-4-(methoxymethoxy)phenyl)propanoate 13 (also referred to as Fmoc-3-iodo-D-Tyr(MOM)-OMOM). The reaction takes place in dichloromethane (DCM) in the presence of diisopropylethylamine (DIPEA) and tetrabutylammoniumchloride (TBACl). Then, in step (c) compound 13 is reacted to the target compound 1D. The reaction is done in a mixture of tetrahydrofuran (THF), water and pyridine.
[0093] Analysis of the compound prepared was done both by HPLC analysis and LC-MS analysis.
a) Synthesis of Fmoc-3-iodo-D-Tyr-OH (12)
[0094] 3-Iodo-D-Tyr-OH 11 (5 g, 16.28 mmol) was suspended in 50 ml of an aqueous Na.sub.2CO.sub.3 solution (1.726 g, 16.28 mmol) in an argon atmosphere. 10 ml of dioxane were added and the yellow solution was cooled in an ice water bath. Fmoc-OSu (5.492 g, 16.28 mmol) dissolved in 50 ml of 1,4-dioxane was added dropwise via a dropping funnel under an argon atmosphere. Upon addition the reaction mixture was stirred in an ice water bath for 1 hr, then at room temperature. After 17 hrs thin layer chromatography (TLC with (DCM/methanol (MeOH), 9:1 as the eluant) showed the complete conversion to the desired product Fmoc-3-iodo-D-Tyr-OH. 100 ml of H.sub.2O were added and the mixture was cooled in an ice water bath. 30% HCl (app. 4 ml) were added until a pH of 2 to 3 was reached. The mixture was extracted with ethyl acetate (3150 ml), the combined organic phases were washed with H.sub.2O (2150 ml) and saline (1150 ml), dried over Na.sub.2SO.sub.4 and filtered (filter pore size 4). The solvent was removed by rotation evaporation, the residue was dried under high vacuum. Yield: 9.5 g (110%, quant.) of a white foamy solid. The crude product was used in the next step without any purification.
[0095] HPLC: t.sub.R=7.26 min LC-MS: t.sub.R=12.57 min, m/z=530.05 [M+H].sup.+, 1059.16 [2M+H].sup.+. .sup.1H NMR (DMSO-d.sup.6, 500 MHz): 12.70 (br, 1H), 10.12 (s, 1H), 7.88 (m, 2H), 7.72-7.60 (m, 4H), 7.43-7.39 (m, 2H), 7.34-7.28 (m, 2H), 7.09 (m, 1H), 6.79 (m, 1H), 4.21-4.18 (m, 3H), 4.10-5.05 (m, 1H), 2.97-2.93 (m, 1H), 2.75-2.70 (m, 1H).
b) Synthesis of Fmoc-3-iodo-D-Tyr(MOM)-OMOM (13)
[0096] Fmoc-3-iodo-D-Tyr-OH 12 (9.5 g, i.e. 8.62 g, 16.28 mmol100%) was suspended in 120 ml of DCM (anhydrous) under an argon atmosphere. DIPEA (5.673 ml, 32.57 mmol, 2 eq.) was added, what after stirring for 10 min at room temperature resulted in a yellow solution. TBACl (453 mg, 1.628 mmol, 0.1 eq.) was added, and the mixture was cooled in an ice-cooled water bath. Methoxymethylbromide (MOMBr) (2.658 ml, 32.57 mmol, 2 eq.) diluted in 30 ml of DCM (anhydrous) was added dropwise via a dropping funnel under an argon atmosphere (gassing). After having completed the addition the reaction mixture was stirred with ice cooling. After one hour stirring was continued for further 18 hrs at room temperature. TLC (DCM/MeOH, 50:1) showed a complete conversion. 100 ml of H.sub.2O were added, and the mixture was vigorously stirred at room temperature. After 1 hr the phases were separated from each other in a separatory funnel. The aqueous phase was extracted several times each with 150 ml of DCM. The combined organic phases were washed with 1 N HCl (2150 ml) and saline (150 ml), dried over Na.sub.2SO.sub.4 and filtered (filter pore size 4). The solvent was removed in vacuum; the remaining residue was dried in high vacuum. Yield: 11 g (109%, quant.) of a white foamy solid. The crude product was used in the next step without any purification.
[0097] HPLC: t.sub.R=8.97 min LC-MS: t.sub.R=14.76 min, m/z=618.12 [M+H].sup.+, 1235.32 [2M+H].sup.+.
c) Synthesis of Fmoc-3-iodo-D-Tyr(MOM)-OH (1D)
[0098] Fmoc-3-iodo-D-Tyr(MOM)-OMOM 13 was dissolved in 140 ml of THF (p.a.). During stirring a mixture of 400 ml of H.sub.2O and 10 ml of pyridine was added. Ca. 100 ml of THF (p.a.) were added until a clear mixture was obtained. The mixture was refluxed under vigorous stirring in an oil bath (70 C.). After 64 hrs HPLC (214 nm) showed a complete conversion of the starting material (t.sub.R=8.96 min) to the product Fmoc-3-iodo-D-Tyr(MOM)-OH. The solvent (THF) was evaporated in vacuum. The mixture was laced with 2 N HCl (app. 120 ml) under ice cooling. The pH of the solution was between pH 4 and pH 5. The mixture was extracted with DCM (3150 ml), the combined organic phases were washed with 0.5 N HCl (2150 ml) and saturated saline (150 ml), dried over Na.sub.2SO.sub.4 and filtered. The solvent was evaporated in vacuum, the remaining residue was dried in high vacuum. Yield: 9.7 g (104%, quant.) of a white foamy solid. The crude product was purified by column chromatography (yield: 4.6 g, purity by HPLC (214 nm): >95%).
[0099] m/z=574.11 [M+H].sup.+, 1147.26 [2M+H].sup.+. .sup.1H-NMR (400 MHz, CDCl.sub.3) (ppm): 7.752 (d, 2H), 7.610 (s, 1H), 7.549 (m, 2H), 7.387 (t, 2H), 7.307 (m, 2H), 7.042 (d, 1H), 6.960 (d, 2H), 5.185 (s, 2H), 4.697 (m, 1H), 4.444 (m, 1H), 4.336 (m, 1H), 4.201 (m, 1H), 3.483 (s, 3H), 3.131 (m, 1H), 3.004 (m, 1H).
EXAMPLE 2
Synthesis of boc-3-iodo-D-Tyr(MOM)-OH (5D)
[0100] The synthesis of boc-3-iodo-D-Tyr(MOM)-OH was carried out as described in scheme B2:
##STR00037##
[0101] In step (a) (R)-2-amino-3-(4-hydroxy-3-iodophenyl)propionic acid 11 (also referred to as 3-iodo-D-tyrosine or 3-iodo-D-Tyr-OH) was reacted with di-tert-butyldicarbonate (Boc.sub.2O) to obtain (R)-2-((tert-butoxycarbonyl)amino)-3-(4-hydroxy-3-iodophenyl)propionic acid 22 (also referred to as boc-3-iodo-D-Tyr-OH). The reaction takes place in a mixture of water, tetrahydrofuran and triethylamine Then, in step (b) compound 22 is reacted with methoxymethyl bromide (CH.sub.3OCH.sub.2Br) to methoxymethyl-(R)-2-((tert-butoxycarbonyl)amino)-3-(3-iodo-4-(methoxymethoxy)phenyl)propanoate 23 (also referred to as boc-3-iodo-D-Tyr(MOM)-OMOM). The reaction takes place in dichloromethane (DCM) in the presence of diisopropylethylamine (DIPEA) and tetrabutylammonium chloride (TBACl). Then, in step (c) compound 23 is reacted to the target compound 5D. The reaction is done in a mixture of tetrahydrofuran (THF), water and pyridine.
a) Synthesis of boc-3-iodo-D-Tyr-OH (22)
[0102] 3-Iodo-D-Tyr-OH 11 (16.28 mmol) was dissolved in 150 ml of a mixture of THF/H.sub.2O (1:1) and TEA (4.44 ml, 32.56 mmol, 2 eq.) was added dropwise. The mixture was cooled on ice to 0 C. Boc.sub.2O (3.63 ml, 17.9 mmol, 1.1 eq.) was melt in the water bath at 30 C. and subsequently dissolved in 20 ml of THF. The solution was transferred to a dropping funnel and added dropwise over a period of 30 minutes. After one hour the ice bath was removed and the reaction mixture was stirred overnight at room temperature. The complete conversion was controlled by mans of HPLC. THF was removed in vacuum. The aqueous solution was adjusted to pH 3-4 with 1 M HCl and extracted three times with 150 ml of ethyl acetate each. The combined organic phases were dried over sodium sulphate and the solvent was removed in vacuum. The product was dried in high vacuum. The purity of the synthesis product (boc-3-iodo-D-Tyr-OH 22) was determined by HPLC (>95%).
b) Synthesis of boc-3-iodo-D-Tyr(MOM)-OMOM (23)
[0103] Boc-3-iodo-D-Tyr-OH 22 (16.28 mmol) was dissolved in 120 ml of dry DCM. DIPEA (5.67 ml, 32.56 mmol, 2 eq.) and tetrabutylammonium chloride (0.453 g, 1.63 mmol, 0.1 eq.) were added. A solution of methoxymethyl bromide (2.657 ml, 32.56 mmol, 2 eq.) in 30 ml of DCM (anhydrous) was slowly added dropwise to an ice-cooled solution of boc-3-iodo-D-Tyr-OH over a period of 30 minutes. After one hour the ice bath was removed and subsequently stirred overnight at room temperature. After having water added and subsequently separated and dried the organic phase the organic phase was evaporated in vacuum. Complete conversion was controlled by means of HPLC. The product boc-3-iodo-D-Tyr(MOM)-OMOM 23 was identified by HPLC (>95%).
c) Synthesis of boc-3-iodo-D-Tyr(MOM)-OH (5D)
[0104] Boc-I-D-Tyr(MOM)-OMOM was dissolved in 20 ml of THF. 20 ml of a 2 M solution of LiOH in water were added and stirred for 2 hours at room temperature. THF was removed in vacuum. 300 ml of DCM and 150 ml of a 5% KHSO.sub.4 solution were added and stirred for 5 minutes. After phase separation the aqueous phase was extracted once with 150 ml of DCM. The combined organic phases were dried over Na.sub.2SO.sub.4 and the solvent was removed in vacuum. The product obtained was lyophilized.
[0105] .sup.1H-NMR (400 MHz, CDCl.sub.3) (ppm): 7.619 (s, 1H), 7.103 (d, 1H), 6.993 (d, 1H), 5.216 (s, 2H), 4.968; 4.54 (m, 1H), 3.504 (s, 3H), 3.138 (m, 1H), 2.993 (m, 1H), 1.440 (s, 9H).
EXAMPLE 3
a) Synthesis of Tripeptides
[0106] To confirm the improved coupling properties of the compounds of general formula I-A according to the invention tripeptides have been prepared. The tripeptides prepared are shown in table 2, wherein Ac designates acetyl, Me methyl, Amb aminomethylbenzoyl and Pbf a 2,2,4,6,7-pentamethyldihydrobenzofurane-5-sulfonyl group.
[0107] For the preparation of the tripeptides P1 and P2 according to the invention either Fmoc-3-iodo-D-Tyr(MOM)-OH (compound 1D) or boc-3-iodo-D-Tyr(MOM)-OH (compound 5D) has been used. Moreover, for comparison tripeptides V1 and V2 have been prepared. Tripeptides V1 and V2 differ from tripetides P1 and P2 by the protection of the phenolic hydroxy group. In the tripetides P1 and P2 the phenolic hydroxy group is protected by a CH.sub.2OCH.sub.3 group (MOM), while in tripeptides V1 and V2 it is not protected.
TABLE-US-00003 TABLE 2 Designation Compound Structure (Sequence) P1
[0108] The tripeptides have been prepared by means of the Fmoc/tBu strategy developed by Merrifield on a chlorotrityl resin which is also referred to as Barlos resin (Barlos, K., et al., Darstellung geschtzter Peptid-Fragmente unter Einsatz substituierter Triphenylmethylharze, Tetrahedron Letters, 1989, 30(30), S. 3943-3946). This allows cleavage of completely protected peptide fragments by means of weakly acidic compounds such as hexafluoroisopropanol (HFIP). Coupling of all amino acid-like components is done by means of diisopropylcarbodiimide (DIC) and hydroxyiminocyano acetic ester (Oxyma). Cleavage of Fmoc-protective groups is done with 20% piperidine in DMF. Cleavage of the peptide from resin was done with 20% 1,1,1,3,3,3-hexafluoropropane-2-ol (HFIP) in DCM.
b) Comparison Tests
[0109] The tripeptides P1 and P2 according to the invention and the tripeptides V1 and V2 for comparison were coupled using diisopropylcarbodiimide (DIC) and hydroxyiminocyano acetic ester (Oxyma) within 60 min.
[0110] For the preparation of tripeptide P1 Fmoc-3-iodo-D-Tyr(MOM)-OH (1D) was coupled to HN-Me-D-Orn(Amb-Ac)-Arg(Pbf) chlorotrityl resin. Coupling was kinetically monitored. The results are shown in table 3.
TABLE-US-00004 TABLE 3 Synthesis of Fmoc-3-iodo-D-Tyr(MOM)-N-Me-D-Orn(Amb-Ac)- Arg(Pbf)-OH (P1) from Fmoc-3-iodo-D-Tyr(MOM)-OH (1D) and H-N-Me-D-Orn(Amb-Ac)-Arg(Pbf) Chlorotrityl Resin Side Time Educt* Product Products (min) (%) P1 (%)** (%) *** 0 100 0 0 15 73 26 0 60 40 60 0 120 14 86 0 720 6 94 0 *Educt is H-N-Me-D-Orn(Amb-Ac)-Arg(Pbf)-OH, since the reduction of Fmoc-3-iodo-D-Tyr(MOM)-OH can only be determined with some effort. **Fmoc-3-iodo-D-Tyr(MOM)-N-Me-D-Orn(Amb-Ac)-Arg(Pbf)-OH (P1) ***It has not been determined which side products are involved.
[0111] For the preparation of tripeptide V1 Fmoc-3-iodo-D-Tyr-OH was coupled to HN-Me-D-Orn(Amb-Ac)-Arg(Pbf) chlorotrityl resin. Coupling was kinetically monitored. The results are shown in table 4.
TABLE-US-00005 TABLE 4 Synthesis of Fmoc-3-iodo-D-Tyr-N-Me-D-Orn(Amb-Ac)- Arg(Pbf)-OH (V1) from Fmoc-3-iodo-D-Tyr-OH and H-N-Me-D-Orn(Amb-Ac)-Arg(Pbf) Chlorotrityl Resin Side Time Educt* Product Products (min) (%) V1 (%)** (%)*** 0 100 0 0 15 81 14.2 4.7 60 65.8 21.9 12.2 120 59.8 26 14.1 720 51.5 29 19.5 *Educt is H-N-Me-D-Orn(Amb-Ac)-Arg(Pbf)-OH, since the reduction of Fmoc-3-iodo-D-Tyr-OH can only be determined with some effort. **Fmoc-3-iodo-D-Tyr-N-Me-D-Orn(Amb-Ac)-Arg(Pbf)-OH (V1) ***It has not been determined which side products are involved.
[0112] For the preparation of tripeptide P2 boc-3-iodo-D-Tyr(MOM)-OH (5D) was coupled to HN-Me-D-Orn(Amb-Ac)-Arg(Pbf) chlorotrityl resin. Coupling was kinetically monitored. The results are shown in table 5.
TABLE-US-00006 TABLE 5 Synthesis of Boc-3-iodo-D-Tyr(MOM)-N-Me-D-Orn(Amb-Ac)- Arg(Pbf)-OH (P2) from Boc-3-iodo-D-Tyr(MOM)-OH and H-N-Me-D-Orn(Amb-Ac)-Arg(Pbf) Chlorotrityl Resin Side Time Educt* Product Products (min) (%) P2 (%)** (%)*** 0 100 0 0 15 87.3 12.17 0 60 37.16 62.84 0 120 13.37 86.63 0 720 0.68 99.32 0 *Educt is H-N-Me-D-Orn(Amb-Ac)-Arg(Pbf)-OH, since the reduction of boc-3-iodo-D-Tyr(MOM)-OH can only be determined with some effort. **boc-3-iodo-D-Tyr(MOM)-N-Me-D-Orn(Amb-Ac)-Arg(Pbf)-OH (P2) ***It has not been determined which side products are involved.
[0113] For the preparation of tripeptide V2 boc-3-iodo-D-Tyr-OH was coupled to HN-Me-D-Orn(Amb-Ac)-Arg(Pbf) chlorotrityl resin. Coupling was kinetically monitored. The results are shown in table 6.
TABLE-US-00007 TABLE 6 Synthesis of boc-3-iodo-D-Tyr-N-Me-D-Orn(Amb-Ac)- Arg(Pbf)-OH (V2) from boc-3-iodo-D-Tyr-OH and H-N-Me-D-Orn(Amb-Ac)-Arg(Pbf) Chlorotrityl Resin Side Time Educt* Product Products (min) (%) V2 (%)** (%)*** 0 100 0 0 15 93.2 5.7 1.06 60 73.3 16.1 10.6 120 65.2 19.8 15 720 53.74 18.56 27.7 *Educt is H-N-Me-D-Orn(Amb-Ac)-Arg(Pbf)-OH, since the reduction of boc-3-iodo-D-Tyr-OH can only be determined with some effort. **boc-3-iodo-D-Tyr-N-Me-D-Orn(Amb-Ac)-Arg(Pbf)-OH ***It has not been determined which side products are involved.
[0114] Preparation of tripeptides P1 and P2 according to the invention and tripeptides V1 and V2 for comparison shows that both using Fmoc-3-iodo-D-Tyr(MOM)-OH (1D) and boc-3-iodo-D-Tyr(MOM)-OH (5D) results in the target compound of high purity and yield. Using the iodotyrosine derivatives that are unprotected in the side chain resulted in a significantly reduced yield and formation of non-specified side products. Tripeptides P1 and P2 give evidence for the increased efficiency of peptide synthesis resulting from the use of the tyrosine derivatives with protected phenolic hydroxy function according to the invention.
EXAMPLE 4
Synthesis of Pentixather
[0115] Pentixather could be prepared with great efficiency by means of the amino acid Fmoc-3-iodo-D-Tyr(MOM)-OH (1D), while the use of the unprotected amino acid Fmoc-3-iodo-D-Tyr-OH resulted in no or only little conversion.
EXAMPLE 5
Synthesis of PSMAI&T
[0116] Synthesis of the compound Glu-CO-Lys[(Sub)DLys-DPhe-DTyr(3I)-DOT-AGA]trifluoroacetate (PSMAI&T) (Wirtz, M., et al., Synthesis and in vitro and in vivo evaluation of urea-based PSMA inhibitors with increased lipophilicity. EJNMMI Research, 2018. 8(1): p. 84) run in analogy to the synthesis of pentixather with greater efficiency and significantly improved purity of the end product when using boc-3-iodo-D-Tyrosin(MOM)-OH (1D) instead of the unprotected derivative.
CITED LITERATURE
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