PROCESS FOR THE SYNTHESIS OF AMIDE BONDS WITH THE AID OF NOVEL CATALYSTS

Abstract

The invention relates to a process for the production of amide bonds, in particular peptide bonds, with the aid of novel amide linking reagents containing an anion of the formula (I), to the novel reagents, and to the preparation thereof.

Claims

1. Process for the production of an amide bond by reaction of an acid with a primary or secondary amine in the presence of a base with the aid of an amide linking reagent, characterised in that use is made of at least one amide linking reagent containing an anion of the formula (I),
[P(C.sub.nF.sub.2n+1).sub.yF.sub.6-y].sup.(I), where n stands on each occurrence, independently, for 1, 2, 3, 4, 5, 6, 7 or 8 and y stands for 1, 2, 3 or 4.

2. Process according to claim 1, in which use is made of amide linking reagents containing anions of the formula (I) in which the variable n stands on each occurrence, independently, for 2, 3 or 4.

3. Process according to claim 1, in which use is made of amide linking reagents containing anions of the formula (I) selected from the group [(C.sub.2F.sub.5).sub.3PF.sub.3].sup., [(C.sub.3F.sub.7).sub.3PF.sub.3].sup., [(C.sub.4F.sub.9).sub.3PF.sub.3].sup., [(C.sub.2F.sub.5).sub.2PF.sub.4].sup., [(C.sub.3F.sub.7).sub.2PF.sub.4].sup., [(C.sub.4F.sub.9).sub.2PF.sub.4].sup., [(C.sub.2F.sub.5)PF.sub.5].sup., [(C.sub.3F.sub.7)PF.sub.5].sup. and [(C.sub.4F.sub.9)PF.sub.5].sup..

4. Process according to claim 1, characterised in that the cation of the amide linking reagent is a uronium, thiouronium, guanidinium, aminium, carbonium, imidazolium or phosphonium cation.

5. Process according to claim 1, characterised in that a peptide bond is produced.

6. Compounds from the following group of compounds, where FAP.sup. stands for an anion of the formula (I), as described in claim 1: ##STR00039## ##STR00040##

7. Compounds according to claim 6, where FAP.sup. stands for [(C.sub.2F.sub.5).sub.3PF.sub.3].sup. Or [(n-C.sub.4F.sub.9).sub.3PF.sub.3].sup..

Description

EXAMPLES

[0068] ##STR00007##

Example A) Synthesis of the Amide Linking Reagents

[0069] Method A: Synthesis from Tetrafluoroborates

[0070] A solution of potassium tris(pentafluoroethyl)trifluorophosphate, K[(C.sub.2F.sub.5).sub.3PF.sub.3] (4.188 g, 8.65 mmol) in acetonitrile (15 ml) is added to a solution of the amide linking reagent containing tetrafluoroborate anions (8.65 mmol) in acetonitrile (15 ml), and the reaction mixture is stirred at 0 C. in an ice bath for two hours. The resultant mixture is filtered. The residue, principally insoluble potassium tetrafluoroborate, is washed three times with 10 ml of cold acetonitrile, and the washing solutions are combined with mother liquor. The acetonitrile is removed from the combined solutions in vacuo, and the residue (FAP-containing peptide linking reagent) is dried in vacuo (10.sup.3 mbar) and subsequently recrystallised.

[0071] Method B: Synthesis from Hexafluorophosphates

[0072] The hexafluorophosphate peptide linking reagent (4.74 mmol) and potassium tris(pentafluoroethyl)trifluorophosphate, K[(C.sub.2F.sub.5).sub.3PF.sub.3] (2.293 g, 4.74 mmol) are suspended in 20 ml of acetonitrile and stirred at room temperature until a clear solution forms. The acetonitrile is removed in vacuo, and the residue is dried in vacuo (10.sup.3 mbar) for two hours. The product is extracted from the residue with the solvent or solvent mixture indicated in Table 1 and subsequently recrystallised.

TABLE-US-00001 TABLE 1 Overview of the synthesis methods, denoted by A or B, for the novel amide linking reagents Solvent or mixture for extraction; Starting amount in Solvent for the Product material Method ml/mmol recrystallisation Yield DBTU- TDBTU A Dichloromethane/ 90% FAP n-hexane STU-FAP TSTU A 86% PfTU- PfTU B Dichloromethane; n-Hexane 97% FAP 6 ml/mmol OTT-FAP HOTT B Dichloromethane; Diethyl ether 82% 3 ml/mmol BTU-FAP HBTU B Dichloromethane 99% with 2% of acetonitrile; 21 ml/mmol BPyU- HBPyU B Dichloromethane; 93% FAP 20 ml/mmol ATU-FAP HATU B Dichloromethane Diethyl ether 52% with 2.5% of acetonitrile; 60 ml/mmol BOP- BOP B Dichloromethane; n-Hexane 93% FAP 6 ml/mmol PyBOP- PyBOP B Dichloromethane; n-Hexane 92% FAP 4 ml/mmol PyAOP- PyAOP B Dichloromethane; n-Hexane 100% FAP 4.3 ml/mmol TFF-FAP TFFH B Dichloromethane; n-Hexane 99% 4.0 ml/mmol COMU- COMU B Dichloromethane; n-Hexane 97% FAP 4.6 ml/mmol

[0073] Characterisation of the Amide Linking Reagents:

O-(3,4-Dihydro-4-oxo-1,2,3-benzotriazin-3-yl)-N,N,N,N-tetramethyluronium tris(pentafluoroethyl)trifluorophosphate (DBTU-FAP)

[0074] Melting point: 124 C.

[0075] Elemental analysis:

[0076] experimental, %: N 9.71, C 30.32, H, 2.15;

[0077] calculated for C.sub.18H.sub.16F.sub.18N.sub.5O.sub.2P, %: N, 9.90, C, 30.56, H, 2.28.

[0078] NMR (25 C., solvent: CD.sub.3CN; in ppm):

[0079] .sup.1H-NMR: 8.39 (d, d, .sup.3J.sub.H,H=8.0 Hz, .sup.4J.sub.H,H=1.4 Hz, 1H), 8.36 (d, m, .sup.3J.sub.H,H=8.4 Hz, 1H), 8.21 (t, d, .sup.3J.sub.H,H=7.6 Hz, .sup.4J.sub.H,H=1.6 Hz, 1H), 8.04 (t, d, .sup.3J.sub.H,H=7.6 Hz, .sup.4J.sub.H,H=1.2 Hz, 1H), 3.23 (s, 12H);

[0080] .sup.13C{.sup.1H}-NMR: 162.89, 152.34, 144.99, 137.84, 135.23, 130.49, 126.76, 123.16, 41.41:

[0081] .sup.19F-NMR: 44.80 (d, m, .sup.1J.sub.F,P=890 Hz, 1F, PF), 80.89 (m, 3F, CF.sub.3), 82.58 (m, 6F, 2CF.sub.3), 88.21 (d, m, .sup.1J.sub.F,P=902 Hz, 2F, PF), 116.27 (br d, .sup.2J.sub.F,P=82.9 Hz, 2F, CF.sub.2), 116.89 (d, m, .sup.2J.sub.F,P=97.7 Hz, 4F, 2CF.sub.2):

[0082] .sup.31P-NMR: 147.91 (d, t, t, quin, .sup.1J.sub.P,F=902 Hz, .sup.1J.sub.P,F=889.2 Hz, .sup.2J.sub.P,F=97.4 Hz, .sup.2J.sub.P,F=83.8 Hz, 1P).

[0083] Crystal data: (T=150 C.): monoclinic, a=10.1170(5) {acute over ()}, b=15.3535(12) {acute over ()}, c=16.7415(10) {acute over ()}, =91.332(6).

O(N-Succinimidyl)-N,N,N,N-tetramethyluronium tris(pentafluoroethyl)trifluorophosphate (STU-FAP)

[0084] Melting point: 143 C.

[0085] Elemental analysis:

[0086] experimental, %: N, 6.19, C, 27.19, H, 2.41;

[0087] calculated for C.sub.15H.sub.16F.sub.18N.sub.3O.sub.3P, %: N, 6.40, C, 27.33. H, 2.45.

[0088] NMR (25 C., solvent: CD.sub.3CN; in ppm):

[0089] .sup.1H-NMR: 3.13 (s, 12H), 2.84 (s, 4H);

[0090] .sup.13C{.sup.1H} NMR: 170.90, 163.19, 41.18, 26.59;

[0091] .sup.19F NMR: 44.78 (d, m, .sup.1J.sub.F,P=890.6 Hz, 1F, PF), 80.86 (m, 3F, CF.sub.3), 82.55 (m, 6F, 2CF.sub.3), 88.20 (d, m, .sup.1J.sub.F,P=902.2 Hz, 2F, PF), 116.24 (br d, .sup.2J.sub.F,P=83.0 Hz, 2F, CF.sub.2), 116.85 (d, m, .sup.2J.sub.F,P=97.8 Hz, 4F, 2CF.sub.2); .sup.31P NMR: 147.89 (d, t, t, quin, .sup.1J.sub.P,F=902.3 Hz, .sup.1J.sub.P,F=889.5 Hz, .sup.2J.sub.P,F=97.7 Hz, .sup.2J.sub.P,F=82.9 Hz, 1P).

O-Pentafluorophenyl-N,N,N,N-tetramethyluronium tris(pentafluoroethyl)trifluorophosphate (PfTU-FAP)

[0092] Melting point: 49 C.

[0093] Elemental analysis:

[0094] experimental, %: N, 3.87, C, 28.05, H, 1.51;

[0095] calculated for C.sub.17H.sub.12F.sub.23N.sub.2OP, %: N, 3.85, C, 28.04, H, 1.66.

[0096] NMR (25 C., solvent: CD.sub.3CN; in ppm):

[0097] .sup.1H NMR: 3.12 (s, 12H);

[0098] .sup.13C{.sup.1H}: 161.64, 41.24;

[0099] .sup.19F NMR: 44.83 (d, m, .sup.1J.sub.F,P=889.6 Hz, 1F, PF), 80.93 (m, 3F, CF.sub.3), 82.62 (m, 6F, 2CF.sub.3), 88.23 (d, m, .sup.1J.sub.F,P=902.3 Hz, 2F, PF), 116.30 (br d, .sup.2J.sub.F,P=83.2 Hz, 2F, CF.sub.2), 116.92 (d, m, .sup.2J.sub.F,P=97.7 Hz, 4F, 2CF.sub.2), 157.94 (d, .sup.3J.sub.F,F=18.2 Hz, 2F, CF), 159.02 (t, .sup.3J.sub.F,F=21.0 Hz, 1F, CF), 161.55 (d, t, .sup.3J.sub.F,F=10.4 Hz, .sup.3J.sub.F,F=10.4 Hz, 2F, CF);

[0100] .sup.31P NMR: 147.89 (d, t, t, quin, .sup.1J.sub.P,F=902.5 Hz, .sup.1J.sub.P,F=889.4 Hz, .sup.2J.sub.P,F=97.6 Hz, .sup.2J.sub.P,F=83.1 Hz, 1P).

S-(1-Oxido-2-pyridyl)-N,N,N,N-tetramethylthiouronium tris(pentafluoroethyl)trifluorophosphate (OTT-FAP)

[0101] Melting point: 84 C.

[0102] Elemental analysis:

[0103] experimental, %: N, 6.51, C, 28.79, H, 2.29, S 4.69;

[0104] calculated for C.sub.16H.sub.15F.sub.18N.sub.3OPS, %: N, 6.27, C, 28.67, H, 2.26, S 4.78.

[0105] NMR (25 C., solvent: CD.sub.3CN; in ppm):

[0106] .sup.1H NMR: 8.32 (d, d, .sup.3J.sub.H,H=6.4 Hz, .sup.4J.sub.H,H=1.2 Hz, 1H), 7.73 (d, d, .sup.3J.sub.H,H=7.7 Hz, .sup.4J.sub.H,H=2.2 Hz, 1H), 7.47 (t, d, 3J.sub.H,H=5.9 Hz, .sup.4J.sub.H,H=2.3 Hz), 7.42 (t, d, .sup.3J.sub.H,H=7.7 Hz, .sup.4J.sub.H,H=1.3 Hz, 1H), 3.20 (s, 12H);

[0107] .sup.13C{.sup.1H} NMR: 172.21, 141.27, 131.56, 128.40, 127.53, 44.45;

[0108] .sup.19F NMR (CD.sub.3CN, 25 C.): 44.75 (d, m, .sup.1J.sub.F,P=889.8 Hz, 1F, PF), 80.83 (m, 3F, CF.sub.3), 82.52 (m, 6F, 2CF.sub.3), 88.16 (d, m, .sup.1J.sub.F,P=902.3 Hz, 2F, PF), 16.21 (br d, .sup.2J.sub.F,P=83.1 Hz, 2F, CF.sub.2), 116.81 (d, m, .sup.2J.sub.F,P=97.7 Hz, 4F, 2CF.sub.2); .sup.31P NMR: 147.87 (d, t, t, quin, .sup.1J.sub.P,F=902.4 Hz, J.sub.P,F=889.6 Hz, .sup.2J.sub.P,F=97.7 Hz, .sup.2J.sub.P,F=82.8 Hz, 1P).

1-(Dimethylamino(dimethylammonium-1-ylidene)methyl)-1H-benzo[d]-1,2,3-triazole 3-oxide tris(pentafluoroethyl)trifluorophosphate (BTU-FAP)

[0109] Melting point: 135 C.

[0110] Elemental analysis:

[0111] experimental, %: N, 10.03, C, 30.00; H, 2.23;

[0112] calculated for C.sub.17H.sub.16F.sub.18N.sub.5OP, %: N, 10.31, C, 30.06, H, 2.37.

[0113] NMR (25 C., solvent: CD.sub.3CN; in ppm):

[0114] .sup.1H NMR: 8.05 (d, t, .sup.3J.sub.H,H=8.4 Hz, .sup.4J.sub.H,H=0.9 Hz, 1H), 7.94 (t, t, .sup.3J.sub.H,H=7.4 Hz, J=1.0 Hz, 1H), 7.71 (d, d, d, .sup.3J.sub.H,H=8.1 Hz, .sup.3J.sub.H,H=7.3 Hz, .sup.4J.sub.H,H=0.5 Hz, 1H), 7.64 (d, m, .sup.3J.sub.H,H=8.5 Hz, 1H), 3.38 (s, 6H), 3.03 (s, 6H);

[0115] .sup.13C{.sup.1H} NMR: 152.14, 134.44, 134.40, 128.43, 117.06, 115.01, 42.96, 42.64.

[0116] .sup.19F NMR: 44.78 (d, m, .sup.1J.sub.F,P=890.3 Hz, 1F, PF), 80.87 (m, 3F, CF.sub.3), 82.57 (br m, 6F, 2CF.sub.3), 88.19 (d, m, .sup.1J.sub.F,P=902.2 Hz, 2F, PF), 116.26 (br d, .sup.2J.sub.F,P=83.9 Hz, 2F, CF.sub.2), 116.85 (d, m, .sup.2J.sub.F,P=98.3 Hz, 4F, 2CF.sub.2);

[0117] .sup.31P NMR: 147.88 (d, t, t, quin, .sup.1J.sub.P,F=902.1 Hz, .sup.1J.sub.P,F=889.0 Hz, 2J.sub.P,F=96.6 Hz, 2J.sub.P,F=83.8 Hz, 1P).

1-(Pyrrolidino(pyrrolidinium-1-ylidene)methyl)-1H-benzo[d]-1,2,3-triazole 3-oxide tris(pentafluoroethyl)trifluorophosphate (BPyU-FAP)

[0118] Melting point: 173 C. (decomposition).

[0119] Elemental analysis:

[0120] experimental, %: N, 9.58, C, 34.76, H, 2.98;

[0121] calculated for C.sub.21H.sub.20F.sub.18N.sub.5OP, %: N, 9.58, C, 34.49, H, 2.78.

[0122] NMR (25 C., solvent: CD.sub.3CN; in ppm):

[0123] .sup.1H NMR: 8.06 (d, .sup.3J.sub.H,H=8.4 Hz, 1H), 7.94 (d, d, d, .sup.3J.sub.H,H=8.4 Hz, .sup.3J.sub.H,H=7.2 Hz, .sup.4J.sub.H,H=1.0 Hz, 1H), 7.70 (br t, .sup.3J.sub.H,H=7.7 Hz, 1H), 7.66 (d, .sup.3J.sub.H,H=8.5, 1H), 3.93 (br m, 4H), 3.67 (very br m, 2H), 3.46 (very br m, 2H), 2.17 (very br m, 4H), 1.99 (very br m, 4H);

[0124] .sup.13C{.sup.1H} NMR: 146.27, 134.61, 133.81, 133.44, 128.01, 117.08, 114.35, 54.04 (br), 52.75 (br), 26.91 (br), 25.17 (br);

[0125] .sup.19F NMR: 44.81 (d, m, .sup.1J.sub.F,P=889.4 Hz, 1F, PF), 80.90 (m, 3F, CF.sub.3), 82.60 (m, 6F, 2CF.sub.3), 88.21 (d, m, .sup.1J.sub.F,P=902.3 Hz, 2F, PF), 116.29 (br d, .sup.2J.sub.F,P=82.0 Hz, 2F, CF.sub.2), 116.90 (dm, .sup.2J.sub.F,P=97.8 Hz, J=8.1 Hz, 4F, 2CF.sub.2);

[0126] .sup.31P NMR: 147.92 (d, t, t, quin, .sup.1J.sub.P,F=903.3 Hz, .sup.1J.sub.P,F=889.5 Hz, .sup.2J.sub.P,F=97.5 Hz, .sup.2J.sub.P,F=83.2 Hz, 1P).

[0127] Crystal data: (T=150 C.): monoclinic, a=8.8373(5) {acute over ()}, b=31.0766(19) {acute over ()}, c=10.4906(6) {acute over ()}, =110.133(6).

1-(Dimethylamino(dimethylammonium-1-yliden)methyl)-1H-azabenzo-[d][1,2,3]triazole 3-oxide tris(pentafluoroethyl)trifluorophosphate (ATU-FAP)

[0128] Melting point: >140 C. (decomposition).

[0129] Elemental analysis:

[0130] experimental, %: N, 12.27, C, 28.29, H, 2.02;

[0131] calculated for C.sub.16H.sub.15F.sub.18N.sub.6OP, %: N, 12.35, C, 28.25, H, 2.22.

[0132] NMR (25 C., solvent: CD.sub.3CN; in ppm):

[0133] .sup.1H NMR: 8.84 (d, d, .sup.3J.sub.H,H=4.5 Hz, .sup.4J.sub.H,H=1.1 Hz, 1H), 8.12 (d, d, .sup.3J.sub.H,H=8.6 Hz, .sup.4J.sub.H,H=1.3 Hz, 1H), 7.93 (d, d, .sup.3J.sub.H,H=8.6 Hz, .sup.4J.sub.H,H=4.5 Hz, 1H), 3.37 (s, 6H), 3.04 (s, 6H);

[0134] .sup.13C{.sup.1H} NMR: 152.19, 150.87, 144.97, 128.85, 128.29, 125.00, 43.09, 42.69;

[0135] .sup.19F NMR: 44.80 (d, m, .sup.3J.sub.F,P=889.5 Hz, 1F, PF), 80.90 (m, 3F, CF.sub.3), 82.59 (br m, 6F, 2CF.sub.3), 88.21 (d, m, .sup.3J.sub.F,P=902.2 Hz, 2F, PF), 116.28 (br d, .sup.2J.sub.F,P=83.0 Hz, 2F, CF.sub.2), 116.89 (d, m, .sup.2J.sub.F,P=97.7 Hz, 4F, 2CF.sub.2);

[0136] .sup.31P NMR: 147.88 (d, t, t, quin, J.sub.P,F=902.6 Hz, J.sub.P,F=889.2 Hz, .sup.2J.sub.P,F=98.8 Hz, .sup.2J.sub.P,F=83.5 Hz, 1P).

(Benzotriazol-1-yloxy)tris(dimethylamino)phosphonium tris(pentafluoroethyl)trifluorophosphate (BOP-FAP)

[0137] Melting point: 91 C.

[0138] Elemental analysis:

[0139] experimental, %: N, 10.99, C, 29.14, H, 3.11;

[0140] calculated for C.sub.18H.sub.22F.sub.18N.sub.6OP.sub.2, %: N, 11.32, C, 29.12, H, 2.99.

[0141] NMR (25 C., solvent: CD.sub.3CN; in ppm):

[0142] .sup.1H NMR: 8.16 (d, t, .sup.3J.sub.H,H=8.5 Hz, .sup.4J.sub.H,H=0.9 Hz, 1H), 7.85-7.75 (m 2H), 7.62 (d, d, d, .sup.3J.sub.H,H=8.4 Hz, .sup.3J.sub.H,H=6.5 Hz, .sup.4J.sub.H,H=1.5 Hz, 1H), 2.84 (d, .sup.3J.sub.H,P=10.6, 18H);

[0143] .sup.13C{.sup.1H} NMR: 144.14, 131.58, 129.01, 127.25, 121.71, 109.27, 38.96 (d, .sup.2J.sub.C,P=4.3 Hz, CH.sub.3).

[0144] .sup.19F NMR: 44.79 (d, m, .sup.1J.sub.F,P=889.5 Hz, 1F, PF), 80.88 (m, 3F, CF.sub.3), 82.57 (m, 6F, 2CF.sub.3), 88.20 (d, m, .sup.1J.sub.F,P=898.5 Hz, 2F, PF), 116.26 (br d, .sup.2J.sub.F,P=82.8 Hz, 2F, CF.sub.2), 116.87 (d, m, .sup.2J.sub.F P=97.7 Hz, 4F, 2CF.sub.2);

[0145] .sup.31P NMR: 43.67 (m, 1P), 147.91 (d, t, t, quin, .sup.1J.sub.P,F=902.7 Hz, .sup.1J.sub.P,F=889.2 Hz, .sup.2J.sub.P,F=97.5 Hz, .sup.2J.sub.P,F=83.7 Hz, 1P).

(Benzotriazol-1-yloxy)tris(pyrrolidino)phosphonium tris(pentafluoroethyl)trifluorophosphate (PyBOP-FAP)

[0146] Melting point: 66 C.

[0147] Elemental analysis:

[0148] experimental, %: N, 9.72, C, 34.55, H, 3.30;

[0149] calculated for C.sub.24H.sub.28F.sub.18N.sub.6OP.sub.2, %: N, 10.24, C, 35.13, H, 3.44.

[0150] NMR (25 C., solvent: CD.sub.3CN; in ppm):

[0151] .sup.1H NMR: 8.12 (d, t, .sup.3J.sub.H,H=8.5 Hz, .sup.4J.sub.H,H=0.8 Hz, 1H), 7.80-7.70 (m 2H), 7.59 (d, d, d, .sup.3J.sub.H,H=8.4 Hz, .sup.3J.sub.H,H=5.6 Hz, .sup.4J.sub.H,H=2.4 Hz, 1H), 3.34 (m, 12H), 1.88 (m, 12H);

[0152] .sup.13C{.sup.1H} NMR: 144.07 (d, .sup.4J.sub.C,P=0.4 Hz), 131.29, 128.92 (d, .sup.3J.sub.C,P=0.9 Hz), 127.16, 121.57, 109.38, 49.24 (d, .sup.2J.sub.C,P=4.9 Hz), 26.80 (d, .sup.3J.sub.C,P=9.2 Hz);

[0153] .sup.19F NMR: 44.81 (d, m, .sup.1J.sub.F,P=889.6 Hz, 1F, PF), 80.90 (m, 3F, CF.sub.3), 82.60 (m, 6F, 2CF.sub.3), 88.22 (d, m, .sup.1J.sub.F,P=902.2 Hz, 2F, PF), 116.29 (br d, .sup.2J.sub.F,P=83.1 Hz, 2F, CF.sub.2), 116.90 (d, m, .sup.2J.sub.F,P=97.8 Hz, 4F, 2CF.sub.2);

[0154] .sup.31P NMR: 31.01 (br s, 1P), 147.89 (d, t, t, quin, J.sub.P,F=902.6 Hz, J.sub.P,F=889.7 Hz, .sup.2J.sub.P,F=97.0 Hz, .sup.2J.sub.P,F=83.7 Hz, 1P).

(7-Azabenzotriazol-1-yloxy)tris(pyrrolidino)phosphonium tris(pentafluoroethyl)trifluorophosphate (PyAOP-FAP)

[0155] Melting point: 77 C.

[0156] Elemental analysis: experimental, %: N, 11.77, C, 33.68, H, 3.39;

[0157] calculated for C.sub.23H.sub.27F.sub.18N.sub.7OP.sub.2, %: N, 11.94, C, 33.63, H, 3.31.

[0158] NMR (25 C., solvent: CD.sub.3CN; in ppm):

[0159] .sup.1H NMR: 8.84 (d, .sup.3J.sub.H,H=4.5 Hz, 1H), 8.54 (d, .sup.3J.sub.H,H=8.4 Hz, 1H), 7.62 (d, d, .sup.3J.sub.H,H=8.4 Hz, .sup.3J.sub.H,H=5.6 Hz, 1H), 3.37 (m, 12H), 1.88 (m, 12H); .sup.13C{.sup.1H} NMR: 154.25, 141.05, 135.92, 131.17, 123.32, 49.26 (d, .sup.2J.sub.C,P=4.5 Hz), 26.84 (d, .sup.3J.sub.C,P=9.3 Hz);

[0160] .sup.19F NMR: 44.78 (d, m, .sup.1J.sub.F,P=889.7 Hz, 1F, PF), 80.85 (m, 3F, CF.sub.3), 82.54 (m, 6F, 2CF.sub.3), 88.17 (d, m, .sup.1J.sub.F,P=902.4 Hz, 2F, PF), 116.24 (br d, .sup.2J.sub.F,P=82.7 Hz, 2F, CF.sub.2), 116.85 (d, m, .sup.2J.sub.F,P=97.7 Hz, 4F, 2CF.sub.2);

[0161] .sup.31P NMR: 30.93 (br s, 1P), 147.90 (d, t, t, quin, .sup.1J.sub.P,F=902.4 Hz, .sup.1J.sub.P,F=889.6 Hz, .sup.2J.sub.P,F=97.7 Hz, .sup.2J.sub.P,F=83.1 Hz, 1P).

Fluoro-N,N,N,N-tetramethylformamidinium tris(pentafluoroethyl)-trifluorophosphate (TFF-FAP)

[0162] Melting point: 82 C.

[0163] Elemental analysis: experimental, %: N, 4.92, C, 23.48, H, 2.14;

[0164] calculated for C.sub.11H.sub.12F.sub.19N.sub.2P, %: N, 4.97, C, 23.42, H, 2.14.

[0165] NMR (25 C., solvent: CD.sub.3CN; in ppm):

[0166] .sup.1H NMR: 3.16 (d, .sup.4J.sub.H,F=3.0 Hz, 12H);

[0167] .sup.13C{.sup.1H} NMR: 120.13 (m, .sup.1J.sub.C,F=285.2 Hz), 49.26 (d, .sup.2J.sub.C,P=4.5 Hz), 26.84 (d, .sup.3J.sub.C,P=9.3 Hz), 39.11;

[0168] .sup.19F NMR: 44.77 (d, m, .sup.1J.sub.F,P=889.5 Hz, 1F, PF), 45.17 (tridecet, .sup.4J.sub.F,H=3.0 Hz, 1F, CF), 80.92 (m, 3F, CF.sub.3), 82.61 (m, 6F, 2CF.sub.3), 88.25 (d, m, .sup.1J.sub.F,P=904.2 Hz, 2F, PF), 116.34 (br d, .sup.2J.sub.F,P=82.3 Hz, 2F, CF.sub.2), 116.92 (d, m, .sup.2J.sub.F,P=97.7 Hz, 4F, CF.sub.2);

[0169] .sup.31P NMR: 147.90 (d, t, t, quin, .sup.1J.sub.P,F=904.2 Hz, J.sub.P,F=889.5 Hz, .sup.2J.sub.P,F=97.7 Hz, .sup.2J.sub.P,F=82.3 Hz, 1P).

(1-Cyano-2-ethoxy-2-oxoethylideneaminooxy)dimethylaminomorpholinocarbenium tris(pentafluoroethyl)trifluorophosphate (COMU-FAP)

[0170] Melting point: 79 C.

[0171] Elemental analysis: experimental, %: N, 7.69, C, 29.63, H, 2.44;

[0172] calculated for C.sub.18H.sub.19F.sub.18N.sub.4O.sub.4P, %: N, 7.69, C, 29.68, H, 2.63.

[0173] NMR (25 C., solvent: CD.sub.3CN; in ppm):

[0174] .sup.1H NMR: 4.49 (q, .sup.3J.sub.H,H=7.1 Hz, 2H, CH.sub.2), 3.82 (t, .sup.3J.sub.H,H=4.7 Hz, 4H, CH.sub.2), 3.56 (t, .sup.3J.sub.H,H=4.7 Hz, 4H, CH.sub.2), 3.19 (s, 6H, CH.sub.3), 1.40 (t, .sup.3J.sub.H,H=7.1 Hz, 2H, CH.sub.3);

[0175] .sup.13C{.sup.1H} NMR: 159.82, 155.47, 134.43, 106.05, 65.36, 64.65, 49.36, 40.25, 12.84;

[0176] .sup.19F NMR: 44.83 (d, m, .sup.1J.sub.F,P=889.2 Hz, 1F, PF), 80.86 (m, 3F, CF.sub.3), 82.56 (m, 6F, 2CF.sub.3), 88.26 (d, m, .sup.1J.sub.F,P=901.8 Hz, 2F, PF), 116.24 (br d, .sup.2J.sub.F,P=83.1 Hz, 2F, CF.sub.2), 116.87 (d, m, .sup.2J.sub.F,P=98.2 Hz, 4F, 2CF.sub.2);

[0177] .sup.31P NMR: 147.92 (d, t, t, quin, .sup.1J.sub.P,F=901.8 Hz, .sup.1J.sub.P,F=889.6 Hz, .sup.2J.sub.P,F=98.2 Hz, .sup.2J.sub.P,F=83.1 Hz, 1P).

Example B) Solubility of the Amide Linking Reagents

[0178] All solubility determinations are carried out in a tared gas-tight 4 ml bottle with magnetic stirrer bar. The amide linking reagent (at least 5 mg) is weighed out and a certain amount of the solvent to be investigated is added. The mixture is stirred for 2-5 minutes. If undissolved solid is still present, solvent (50-100 l) is additionally added, and the mixture is stirred again. As soon as a clear solution is present, the experiment is terminated. Table 2 below summarises the solubilities of the peptide linking reagents investigated.

TABLE-US-00002 TABLE 2 solubilities of the amide linking reagents in mg/ml; FAP.sup. in Table 2 denotes [(C.sub.2F.sub.5).sub.3PF.sub.3].sup. Reagent CH.sub.2Cl.sub.2 CH.sub.3CN 9CH.sub.2Cl.sub.2:1CH.sub.3CN THF DMF HDBTU 3.75 240 17 <3.3 250 DBTU-FAP >780 >860 480 >780 >1125 TSTU <1.2 265 2.9 <1.2 220 STU-FAP 3.0 >2000 110 690 >2000 PfTU <1.2 1000 2.5 <1.2 1000 PfTU-FAP 1000 >2000 >2000 1000 >2000 HOTT 59 810 180 <1.2 690 OTT-FAP 690 >2000 >2000 1400 >2000 HBTU <1.1 124 <2.8 <3.6 200 BTU-FAP 6.9 >1040 120 364 >1200 HBPyU 68.3 510 118 <3.3 540 BPyU-FAP 57 >1020 190 510 >1100 HATU <1.2 212 1.2 <1.2 370 ATU-FAP <1.2 >2000 67 670 >2000 BOP >380 510 >335 <4.2 660 BOP-FAP >1040 >700 >800 >1200 >1100 PyBOP 680 830 660 4.3 670 PyBOP- >1650 >1550 >1500 >1500 >1550 FAP PyAOP 1000 1000 670 6.0 670 PyAOP- >2000 >2000 >2000 >2000 >2000 FAP TFFH 220 1360 595 6.3 610 TFF-FAP 1190 4490 >2000 880 >2000 COMU 82 565 294 4.1 530 COMU-FAP 180 905 >2000 349 >1500 Reagent Hexane Toluene HDBTU <1.2 <1.2 DBTU-FAP <1.2 <1.2 TSTU <1.2 <1.2 STU-FAP <1.2 <1.2 PfTU <1.2 <1.2 PfTU-FAP <1.2 <1.2 HOTT <1.2 <1.2 OTT-FAP <1.2 <1.2 HBTU <1.2 <1.2 BTU-FAP <1.2 <1.2 HBPyU <1.2 <1.2 BPyU-FAP <1.2 <1.2 HATU <1.2 <1.2 ATU-FAP <1.2 <1.2 BOP <1.2 <1.2 BOP-FAP <1.2 <1.2 PyBOP <1.2 <1.2 PyBOP-FAP <1.2 5.0 PyAOP <1.2 <1.2 PyAOP-FAP <1.2 b TFFH 2.2 4.8 TFF-FAP 6.2 13.1 COMU <1.2 3.2 COMU-FAP 2.1 4.5 b means that the formation of two liquid phases was observed

[0179] The solubility in the nonpolar solvents hexane and toluene is as expected virtually unchanged, since these are still ionic compounds. However, the tendency of the solubility improvement on comparison of TFFH and TFF-FAP and COMU and COMU-FAP is evident.

Example C) Activation Experiments with Z-Aib-OH

[0180] Z-Aib-OH (N-benzyloxycarbonyl--aminoisobutyric acid) was selected for the activation experiments since it carries a carboxyl group which is not easy to activate, as mentioned above. In a typical experiment, two equivalents of TMP are added to a 0.1 M solution of Z-Aib-OH in THF with one equivalent of amide linking reagent. 20 l of the reaction mixture are removed at certain time intervals (4, 20 and 40 minutes) and dissolved in 0.6-0.7 ml of deuterated chloroform in an NMR tube. The samples are cooled at 00 C. until the NMR-spectroscopic investigation (for about 20-25 minutes). The intensities of the benzyl proton NMR signals of the acid (5.05 ppm) and of the active ester (5.20 ppm) are compared with one another in order to calculate the reaction conversion [L. A. Carpino, A. El-Faham, J. Org. Chem. 1994, 59, 695-698]. All results are summarised in Table 3.

TABLE-US-00003 TABLE 3 Activation of Z-Aib-OH by the amide linking reagents shown in the table Conversion, % Conversion, % for X.sup.- = Reagent Time for X.sup.- = BF.sub.4.sup.- [(C.sub.2F.sub.5).sub.3PF.sub.3].sup.- [00008] 4 minutes 20 minutes 40 minutes 6 36 62 90 95 99 [00009] 4 minutes 20 minutes 40 minutes 0 0 0 26 50 63 Conversion, % Conversion, % for X.sup.- = Reagent Time for X.sup.- = PF.sub.6.sup.- [(C.sub.2F.sub.5).sub.3PF.sub.3].sup.- [00010] 4 minutes 20 minutes 40 minutes 52 80 87 91 95 97 [00011] 4 minutes 20 minutes 40 minutes 3.7 3.7 4.0 8 15 21 [00012] 4 minutes 20 minutes 40 minutes 3 2 4 79 89 95 [00013] 4 minutes 20 minutes 40 minutes 11 21 24 87 97 97 [00014] 4 minutes 20 minutes 40 minutes 0 0 6 100 100 100 [00015] 4 minutes 20 minutes 40 minutes 7 22 43 28 64 76 [00016] 4 minutes 20 minutes 40 minutes 31 65 82 53 83 88 [00017] 4 minutes 20 minutes 40 minutes 62 89 93 71 90 93

[0181] The activation of the acid and thus also the further steps of the amide bond formation in most cases proceeds faster with the amide linking reagents containing the anion [(C.sub.2F.sub.5).sub.3F.sub.3P].sup.. The acceleration of the activation is less pronounced for the amide linking reagents PyBOP-FAP and PyAOP-FAP.

Example D) Synthesis of Ac-Phe-Ala-OMe

[0182] ##STR00018##

[0183] In this reaction, not only the conversion, but also the degree of epimerisation can easily be analysed with the aid of .sup.1H NMR spectroscopy [B. Weinstein, A. E. Pritchard, J. Chem. Soc., Perkin Trans. 1 1972, 1015].

[0184] In a typical experiment, three equivalents of TMP (collidine) are added to an Ac-Phe-OH solution (Ac-Phe-OH=acetyl-protected phenylalanine) in THF (0.2 M) with one equivalent of Ala-OMe hydrochloride (Ala-OMe=alanine methyl ester) and one equivalent of peptide linking reagent. At certain time intervals (5, 10 and 15 minutes), 40 l of the mixture are dissolved in 0.6-0.7 ml of acetonitrile-d.sub.3 in an NMR tube and cooled at 0 C. When all three samples have been prepared, .sup.1H NMR spectra of these samples are measured at 25 C. In these spectra, the doublet of the alanine methyl group is at =1.32 ppm in the dipeptide and at =1.25 ppm in the epimer, the doublet of unreacted Ala-OMe hydrochloride is in the range =1.40-1.50 ppm. The conversion and the degree of epimerisation of the dipeptide is calculated by integration of three signals. The results for the conversion are summarised in Table 4 and the results for the degree of epimerisation are summarised in Table 5.

TABLE-US-00004 TABLE 5 Conversion, % Conversion, % for X.sup.- = Reagent Time for X.sup.- = BF.sub.4.sup.- [(C.sub.2F.sub.5).sub.3PF.sub.3].sup.- [00019] 5 minutes 10 minutes 15 minutes 74 89 94 100 100 100 [00020] 5 minutes 10 minutes 15 minutes 9 11 20 41 55 67 Conversion, % Conversion, % for X.sup.- = Reagent Time for X.sup.- = PF.sub.6.sup.- [(C.sub.2F.sub.5).sub.3PF.sub.3].sup.- [00021] 5 minutes 10 minutes 15 minutes 32 55 68 44 63 73 [00022] 5 minutes 10 minutes 15 minutes 0 1.7 2 5 13 19 [00023] 5 minutes 10 minutes 15 minutes 5.3 6 6.3 93 100 100 [00024] 5 minutes 10 minutes 15 minutes 49 69 76 100 100 100 [00025] 5 minutes 10 minutes 15 minutes 58 69 76 100 100 100 [00026] 5 minutes 10 minutes 15 minutes 44 59 68 67 77 80 [00027] 5 minutes 10 minutes 15 minutes 71 83 87 85 91 94 [00028] 5 minutes 10 minutes 15 minutes 90 97 100 92 100 100

[0185] The conversions are calculated from the integrals of the alanine methyl group of Ala-OMe, dipeptide and epimer.

[0186] An accelerated reaction is observed in the case of all amide linking reagents. The advantage of the novel peptide linking reactions is, in particular, the gain in time in the peptide synthesis through faster reaction times.

[0187] The results for the degree of epimerisation are summarised in Table 5.

TABLE-US-00005 TABLE 5 Epimerisation, Epimerisation, % for X.sup.- = Reagent Time % for X.sup.- = BF.sub.4.sup.- [(C.sub.2F.sub.5).sub.3PF.sub.3].sup.- [00029] 5 minutes 10 minutes 15 minutes 0 0 0.6 0 0 0.4 [00030] 5 minutes 10 minutes 15 minutes b b 3.8 4.0 4.0 5.1 Epimerisation, Epimerisation, % for X.sup.- = Reagent Time % for X.sup.- = PF.sub.6.sup.- [(C.sub.2F.sub.5).sub.3PF.sub.3].sup.- [00031] 5 minutes 10 minutes 15 minutes 3.9 6.0 8.1 6.2 9.0 9.9 [00032] 5 minutes 10 minutes 15 minutes b b b b 9.1 9.1 [00033] 5 minutes 10 minutes 15 minutes b b b 3.1 2.8 3.2 [00034] 5 minutes 10 minutes 15 minutes 8.2 7.3 5.0 3.3 1.8 2.4 [00035] 5 minutes 10 minutes 15 minutes 0 1.0 1.0 1.6 1.2 1.4 [00036] 5 minutes 10 minutes 15 minutes 3.5 3.9 4.2 1.9 3.0 3.4 [00037] 5 minutes 10 minutes 15 minutes 2.2 2.8 3.1 2.4 2.3 2.4 [00038] 5 minutes 10 minutes 15 minutes 0.7 0.7 0.8 0.9 0.6 1.0

[0188] If the letter b is used in the table, it was not possible to calculate the degree of epimerisation owing to inadequate intensity of the signal.

[0189] In some cases, a reduction in the degree of epimerisation is observed.