WO 98/43942
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`28
`
`PCT/SE98/00556
`
`was extracted with toluene and the combined organic layers
`
`were dried (MgSO4) and concentrated. The residue was
`
`treated with sodium hydroxide (1 M) and extracted with
`
`diethyl ether and toluene. The organic layer was dried
`
`5
`
`(MgSO4) and concentrated in vacuo. The residue was
`
`chromatographed on silica (gradient ethyl acetate—methanol
`
`90:10 up to 0.06% NH3 in ethyl acetate-methanol 90:10)
`
`Yield 1 g (18%):
`
`In NMR (CDCl3) 5 0.94 (d, 12H), 2.20 (br,
`
`2H), 2.37 (br, 2H), 3.0 (br, 2H), 4.38 (t, 1H), 5.0 (s,
`
`10
`
`2H), 5.11 (d, 1H), 5.61 (d, 1H), 6.60-6.70 (m, 1H), 6.80
`
`(d, 1H), 7.12-7.19 (m, 12H).
`
`11.2 (S)-N,N-Diisopropyl-3-[2-benzy1oxy-5-(2—hydroxyethy1)—
`
`phenyll-3-phenylpropanamine
`
`15
`
`(S)-N,N-Diisopropyl-3-(2-benzyloxy-5—ethenylphenyl)-3-
`
`phenylpropanamine (l g, 2.34 mmol)
`
`in THF (25 mL) was added
`
`to 9—BBN (0.5 M in THF, 11.7 mL, 5.85 mmol) under nitrogen
`atmosphere at 0 °C. Additional 9—BBN (2.3 mL, 1.2 mmol) was
`
`added after 3 hours of stirring,
`
`the temperature was raised
`
`20
`
`to room temperature and the mixture was stirred for 0.5
`hour. It was then cooled to 0 °C and 1 M sodium hydroxide
`
`(10 mL) was added followed by H20;
`
`(30% in H20, 10 mL).
`
`After 1 hours stirring, water was added and the mixture was
`
`extracted with diethyl ether. The organic layer was washed
`
`25 with water and brine, dried (MgSO4) and concentrated. The
`
`residue was chromatographed on silica (gradient of diethyl
`
`ether to 1% NH3 in diethyl ether). Yield 0.67 g (64%).
`
`1H
`
`NMR (CDCI3) 8 0.90 (d, 12H), 2.10-2.18 (m, 2H), 2.30-2.37
`
`(m, 2H), 2.80 (t, 2H), 2.90-3.0 (m, 2H), 3.80 (br, 2H),
`
`30
`
`4.40 (t, 1H), 5.0 (s, 2H), 5.80 (d, 1H), 7.0 (m, 1H),
`
`7 10-
`
`7.38 (m, 11H).
`
`EXAMPLE 12
`
`(R)-N,N-Diisopropy1-3-[2-hydroxy—5—(2-hydroxyethy1)pheny1]-
`
`35
`
`3—pheny1propanamine hydrochloride
`
`The title compound as well as the starting compounds
`
`were prepared in an analogous manner to the preparation
`
`described in Example 11, with the exception that
`
`(S)—N,N—
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2007 - 1001
`
`Patent Owner, UCB Pharma GmbH – Exhibit 2007 - 1001
`
`

`
`WO 98/43942
`'
`
`29
`
`PCIVSE98/00556
`
`diisopropyl-3-(2-benzyloxy-5-bromophenyl)-3-
`
`phenylpropanamine was changed to (R)-N,N—diisopropyl-3-(2-
`
`benzyloxy—5—bromophenyl)-3-phenylpropanamine (prepared as
`
`described in WO 94/11337, Example 1).
`
`5
`
`Yield 0.35 g (33%); mp 209-215 °C;
`
`[a]D +9.8° (c=1.0,
`
`methanol);
`
`1H NMR (CD3OD) 6 1.29 (d, 12H), 2.40-2.60 (m,
`
`2H), 2.67 (t, 2H), 3.04 (t, 2H), 3.61-3.72 (m, 4H), 4.40
`
`(t, 1H), 6.70 (d, 1H), 6.90 (dd, 1H), 7.0 (s, 1H), 7.18-
`
`7.40 (m, 5H). Anal.
`
`(C23H33NO2‘HCl°0.2H2O) C, H, N.
`
`10
`
`Preparation of starting compounds:
`
`12.1 (R)-N,N—Diisopropy1-3-(2—benzy1oxy—5-ethenylphenyl)-3-
`phenylpropanamine
`
`15
`
`Yield 5.5 g (53%);
`
`1H NMR (CDC13) 8 0.94 (d, 12H),
`
`2.20 (br, 2H), 2.37 (br, 2H), 3.0 (br, 2H), 4.38 (t, 1H),
`
`5.0 (s, 2H), 5.11 (d, 1H), 5.61 (d, 1H), 6.60-6.70 (m, 1H),
`
`6.80 (d, 1H), 7.12-7.19 (m. 12H).
`
`20
`
`12.2 (R)-N,N-Diisopropyl-3-[2-benzy1oxy-5-(2-hydroxyethyl)-
`
`phenyll-3-phenylpropanamine
`
`Yield 1.2 g (75%);
`1H NMR (CDC13) 8 0.89 (d, 12H),
`2.15 (m, 2H), 2.32 (m, 2H), 2.80 (t, 2H), 2.95 (m, 2H),
`
`3.80 (br, 2H), 4.40 (t,\1H), 4.98 (s, 2H), 6.80 (d, 1H),
`
`25
`
`6.96 (m, 1H), 7.10-7.35 (m, 11H).
`
`EXAMPLE 13
`
`(R)-N,N-Diisopropy1-3-(5-acetyl-2-hydroxyphenyl)-3-
`
`phenylpropanamine hydrochloride
`
`30
`
`(R)—N,N—Diisopropyl—3<(5-acetyl-2—benzy1oxyphenyl)-3-
`
`phenylpropanamine (1 g, 2.25 mmol) was treated as described
`
`in Example 11. Yield 0.6 g (68%); mp 105-115 °C;
`
`[alp —
`
`32.6° (c 1.02, methanol);
`
`1H NMR (DMSO-d5) d 1.18-1.28 (m,
`
`12H), 2.5 (m, 3H), 2.50-2.62 (m, 2H), 2.86 (m, 1H), 2.97
`
`35
`
`(m, 1H), 3.58 (m, 2H), 4.38 (t, 1H), 6.99 (d, 1H), 7.2 (m,
`
`1H), 7.29-7.35 (m, 4H), 7.73 (dd, 1H), 7.85 (d, 1H), 9.90
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2007 - 1002
`
`Patent Owner, UCB Pharma GmbH – Exhibit 2007 - 1002
`
`

`
`WO 98/43942
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`PCT/SE98/00556
`
`3 0
`
`(br,
`
`1H), 10.70 (s, 1H). Anal.
`
`(C23H31NO2 °HCl -0 .41-I20) C, H,
`
`N.
`
`5
`
`10
`
`The starting compound (R)~N,N-diisopropyl—3—(5—acetyl-
`
`2—benzyloxypheny1)-3—phenylpropanamine was prepared as
`follows:
`
`13.1 (R)-N,N-Di1sopropy1-3-(5-acetyl-2-benzyloxyphenyl)-3-
`
`phenylpropanamine
`
`To a stirred solution of
`
`(R)—N,N—diisopropyl—3-(2—'
`
`benzyloxy—5—bromophenyl)—3—phenylpropanamine (Example 12)
`
`(10.2 g, 21.23 mmol)
`
`in DMF (100 mL) under nitrogen
`
`atmosphere at room temperature were sequentially added
`
`triethylamine (2.58 g, 25.47 mmol), TlOAc
`
`(6.15 g, 23.35
`
`15
`
`mmol),
`
`isobutylvinylether (14 mL, 106.14 mmol), DPPP (0.87
`
`g, 2.12 mmol) and Pd(OAc)2 (0.24 g, 1.06 mmol). The
`
`reaction temperature was raised to 100 °C and stirred for 3
`hours, cooled to room temperature, filtered and treated
`
`with HCl
`
`(5%, 250 mL) and stirred for another 2 hours. The
`
`reaction mixture was repeatedly extracted with
`
`dichloromethane and the combined organic layers were dried
`
`(MgSO4), filtered and the solvent evaporated. Triethylamine
`
`and DMF were destilled off under reduced pressure to yield
`
`9 g (98%); 1H NMR (CDCI3) 5 1.22 (m, 12H), 2.52-2.70 (m,
`
`7H), 3.40 (br, 2H), 4.34 (t, 1H), 5.10 (S, 1H}. 6.90 (d.
`
`1H), 7.17-7.40 (m, 10H), 7.82 (m,
`
`1H) and 7.92 (S, 1H).
`
`20
`
`25
`
`EXAMPLE 14
`
`N,N-Diisopropy1—3(R)-[2—hydroxy—5-(1-hydroxyethy1)phenyl]-
`
`30
`
`3-phenylpropanamine fumarate
`
`N,N—Diisopropyl-3(R)—[2—benzyloxy-5-(1-hydroxyethyl)—
`
`phenyl]-3-phenylpropanamine (2.7 g,
`
`6.05 mmol) was
`
`hydrogenated over Pd/C (0.27 g,
`
`10%)
`
`in ethanol at
`
`atmospheric pressure for 2 hours. The catalyst was filtered
`
`35
`
`off and the solvent was evaporated. The resulting oil was
`
`chromatographed on silica (toluene—triethy1amine 90:10).
`
`Fumarate salt of the amine was afforded by adding fumaric
`
`acid (0.13 g,
`
`1.13 mmol) dissolved in warm ethanol to a
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2007 - 1003
`
`Patent Owner, UCB Pharma GmbH – Exhibit 2007 - 1003
`
`

`
`WO 98/43942
`’
`
`31
`
`PCT/SE98l00556
`
`solution of the free base in diethyl ether yielding white
`
`crystals (0.44 g, 83%); mp 240-244 °C;
`
`[a]D +9.8° (c 1.02,
`
`methanol);
`
`in NMR (DMSO—d5) 6 1.05 (d, an), 1.26 (dd, 3H),
`
`2.20-2.30 (m, 2H), 2.55-2.67 (m, 2H), 3.30 (m, 2H), 4.32
`
`5
`
`1
`
`(t, 1H), 4.59 (q, 1H), 6.53 (S, 2H), 6.72 (dd, 1H), 6.93
`
`(dd, 0.5H), 7.12-7.17 (m, 1H), 7.21-7.31 (m, SH). Anal.
`
`(C23H33NO2'C4H4O4'0.3H2O) C, H, N.
`
`The starting compound N,N-diisopropyl~3(R)-[2-
`
`10
`
`- benzyloxy-5-(1—hydroxyethyl)pheny1]—3—phenylpropanamine was
`
`prepared as follows:
`
`14.1 N,N-Diisopropyl-3(R)-[2-benzy1oxy-5-(1-hydroxyethy1)—
`
`phenyll-3-phenylpropanamine
`
`'
`
`15
`
`N,N—Diisopropyl~3(R)-(5—acetyl—2—benzyloxyphenyl)-3-
`
`phenylpropanamine, prepared as described in Example 13.1,
`
`(3.5 g, 7.90 mmol) dissolved in dry THF was added to LiA1H4
`
`(0.2 g, 5.41 mmol). After 2 hours of stirring, additional
`
`LiA1H4 (50 mg, 1.32 mmol) was added and the reaction
`
`20 mixture was stirred for 1.5 hours. The reaction was
`
`quenched and the solvent evaporated. The residue was
`
`chromatographed on silica (toluene-E3N 90:10)
`
`to give 2.74
`
`g (78%) of an oil that crystallised slowly upon storage at
`
`room temperature.
`
`25
`
`EXAMPLE 15
`
`(+)-N,N-Diisopropyl-3(R)-[5-(1(R*),2-dihydroxyethyl)-2-
`
`hydroxyphenyll-3-phenylpropanamine fumarate
`
`N,N—Diisopropyl-3(R)-[2-benzyloxy 5—(1(R*),2—
`
`30
`
`dihydroxyethyl)phenyl]—3—phenylpropanamine (0.55 g, 1.2
`
`mmol) was treated in an analogous manner to that described
`
`in Example 14 above, which yielded white crystals, 0.32 g
`
`(55%); mp 196-200 °C;
`
`[a]D +l3.5° (c 1.0, methanol); 1H NMR
`
`(CD3OD) 5 1.28 (m, 12H), 2.40-2.48 (m, 1H), 2.52-2.60 (m,
`1H}. 3.03 (t, 2H), 3.55 (d, 2H), 3.66 (m, 2H), 4.42 (t,
`
`35
`
`1H), 4.57 (t, 1H), 6.7 (s, 2H), 6.79 (d, 1H), 7.05 (dd,
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2007 - 1004
`
`Patent Owner, UCB Pharma GmbH – Exhibit 2007 - 1004
`
`

`
`"W0 98/43942
`
`32
`
`PCT/SE98/00556
`
`1H), 7.15-7.21 (m, 2H), 7.28 (m,
`
`2H), 7.36 (m, 2H). Anal.
`
`(C23H33NO3'C4H4O4) C, H, N.
`
`The starting compound N,N—diisopropyl—3(R)—[2-
`
`benzy1oxy—5~(l(R*),2—dihydroxyethyl)phenyl]-3-
`
`phenylpropanamine was prepared as follows:
`
`15.1 N,N-Diisopropyl-3(R)-[2-benzyloxy-5-(1(R*),2—
`
`dihydroxyethy1)pheny1]-3-phenylpropanamine
`
`10
`
`To an ice—chilled solution of AD—mix—a (5.7 g)
`
`in H20
`
`(20 mL) and t-BuOH (10 mL) was added N,N—diisopropy1-3(R)—
`(2—benzyloxy—5—ethenylphenyl)-3-phenylpropanamine (Example
`
`12.1),
`
`(1.74 g, 4.1 mmol) dissolved in t—BuOH (10 mL).
`
`After 1 hour of stirring,
`
`the ice bath was removed and the
`
`15
`
`"reaction mixture was stirred for additional 21 hours.
`
`Na2SO3 (6 g) was then added and after 1 hours of stirring
`
`the reaction mixture was partioned between H20 and ethyl
`
`acetate. The aqueous layer was extracted 3 times with ethyl
`
`acetate,
`
`the combined organic layers were dried (MgS04) and
`
`20
`
`the solvent evaporated. The residue was chromatographed on
`
`silica (ethyl acetate—triethylamine, 90:10)
`
`to afford 0.55
`
`g.
`
`1H NMR (CDCl3) 5 0.9 (s,
`
`61-1), 0.95 (s, 6H), 2.15-2.20
`
`(m, 2H), 2.30-2.38 (m,
`
`21-1), 2.96 (m, 2H), 3.60-3.70 (m,
`
`2H), 4.41 (t, 1H), 4.75 (m, 1H), 5.0 (s, 2H), 6.85 (d, 1H),
`
`25
`
`7.10-7.35 (m, 12H).
`
`EXAMPLE 16
`
`30
`
`35
`
`(-)-N.N-Diisopropyl-3(R)-[5—(1(S*),2-dihydroxyethyl) 2-
`
`hydroxyphenyll-3-phenylpropanamine fumarate
`
`N,N—Diisopropyl-3(R)-[2-benzy1oxy—5—(l(S*),2-
`
`dihydroxyethyl)phenyl]—3—phenylpropanamine (1.1 g, 2.4
`
`mmol) was treated in an analogous manner to that described
`
`in Example 11 which yielded white crystals,
`
`0.25 g (21%);
`
`mp 208-211 °C;
`
`[alp -8° (C 1.02, methanol);
`
`1H NM (CD3OD)
`
`8 1.28 (m, 12H), 2.39-2.47 (m, 1H), 2.51-2.59 (m, 1H),
`
`3.03
`
`(t, 2H), 3.51-3.53 (m, 2H), 3.67 (m, 2H), 4.42 (t, 1H),
`
`4.54 (dd, 1H), 6.68 (s, 2H), 6.78 (d, 1H), 7.06 (dd, 1H),
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2007 - 1005
`
`Patent Owner, UCB Pharma GmbH – Exhibit 2007 - 1005
`
`

`
`‘W0 98l43942
`
`PCT/SE98/00556
`
`3 3
`
`7.16-7.20 (m, 2H), 7.26 (m,
`
`2H), 7.34-7.36 (m, 2H). Anal.
`
`(C231-I33NO3-C4H4O4) C, H, N.
`
`The starting compound N,N-diisopropyl—3(R)-[2-
`
`benzyloxy-S—(1(S*),2-dihydroxyethy1)pheny1]-3-
`
`phenylpropanamine was obtained by treating N,N—diisopropyl—
`
`3(R)-(2—benzyloxy~5-ethenylphenyl)-3-phenylpropanamine
`
`(obtained in Example 12.1) as described in Example 15.1
`
`above, but with AD-mix—B replacing AD-mix—a. Yield 1.2 g
`
`10
`
`(44%).
`
`EXAMPLE 17
`
`(R)-[N,N-Diisopropy1-3-[2-hydroxy—5-(6—hydroxyhexy1)—
`
`phenyll-3-phenylpropanamine hydrochloride
`
`N,N—Diisopropyl—3(R)-[2-benzyloxy—5—(6—hydroxyhex—1—
`
`eny1)pheny1]-3-phenylpropanamine (0.35 g, 0.72 mmol) was
`
`treated in an analogous manner to that described in Example
`
`14. Yield 0.10 g (31%); mp 147-156 °C;
`
`[a]D +8.2° (C 1.01,
`
`methanol);
`
`1H NMR (CD3OD) 5 1.25-1.32 (m, 16H), 1.45-1.54
`
`(m, 4H), 2.40-2.48 (m, 3H), 2.51-2.59 (m, 1H), 3.0-3.10 (m,
`
`2H), 3.51 (t, QH), 3.68 (m, 2H), 4.40 (t, 1H), 6.72 (d,
`
`1H), 6.86 (dd, 1H), 6.91 (d, 1H), 7.19 (m, 1H), 7.30 (t,
`
`2H), 7.34-7.35 (m, 2H). Anal.
`
`(C27H41NO2'HCl'2H2O) C, N; H:
`
`calcd, 9.6;
`
`found, 8.3.
`
`The starting compound (R)-N,N-diisopropy1—3—[2-
`
`benzyloxy-5-(6-hydroxyhex—1-enyl)phenyl]-3-
`
`phenylpropanamine was prepared as follows:
`
`17.1 (R)-N,N-Diisopropy1-3-(2-benzyloxy-5-formylphenyl)-3-
`
`phenylpropanamine
`
`n—BuLi
`
`(2.5 M in hexane, 19 mL, 47.5 mmol) was added
`
`to a solution of to (R)-N,N—diisopropyl-3-(2—benzy1oxy-5-
`
`bromophenyl)—3- phenylpropanamine (prepared as described in
`
`WO 94/11337, Example 1)
`
`(8.9 g, 18.52 mmol)
`
`in dry diethyl
`
`ether (100 mL) kept at -40 °C under nitrogen atmosphere.
`
`After 1.5 hour of stirring, additional n-BuLi
`
`(10 mL, 25
`
`15
`
`20
`
`25
`
`30
`
`35
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2007 - 1006
`
`Patent Owner, UCB Pharma GmbH – Exhibit 2007 - 1006
`
`

`
`WO 98/43942
`
`PCT/SE98/00556
`
`34
`
`mmol) was added and after 2 hours another n-BuLi
`
`(5 mL,
`
`12.5 mmol) was added. The reaction was then stirred for 15
`
`minutes and DMF (6 mL, 77.8 mmol) was added followed by
`
`additional DMF (5 mL, 64.8 mmol) after 20 minutes of
`
`stirring. The temperature was allowed to rise to room
`
`temperature and after 35 minutes of stirring, NH4C1 (sat.)
`
`was added followed by water and diethyl ether. The layers
`
`were separated and the aqueous layer was extracted with
`
`diethyl ether. The combined organic layers were dried
`
`10
`
`(MgSO4) and the solvent was evaporated. The residue was
`
`chromatographed on silica (toluene—triethy1amine 90:10)
`
`to
`
`afford 8 g (100%) of a yellowish oil;
`
`1H NMR (CDCl3) 8 0.90
`
`(m, 12H), 2.12-2.40 (m, 4H), 2.95 (m, 2H), 4.44 (t, 1H),
`
`5.10 (8, 2H), 6.95 (d, 1H), 7.15-7.36 (m, 10H), 7.70 (dd,
`
`15
`
`1H), 7.91 (s, 1H), 9.88 (s,
`
`IH).
`
`17.2 (R)4N,N-Diisopropy1-3-[2-benzyloxy 5—(5-carboxypent-1-
`
`enyl)pheny1]-3-phenylpropanamine
`
`To a slurry of 4—carboxybutyl
`
`triphenylphosphonium
`
`20
`
`bromide (4.1 g, 9.31 mmol)
`
`in THF (25 mL) at -10 °C under
`
`nitrogen atmosphere was added potassium tert—butoxide (2.1
`
`g, 18.62 mmol). The mixture turned orange and after 10
`
`minutes stirring.
`
`(R)-N,N-diisopropyl-3-(2—benzyloxy-5-
`
`25
`
`in THF
`formylphenyl)—3—phenylpropanamine (2 g, 4.65 mmol)
`(10 mL) was added. After 4 hours of stirring, hydrochloric
`
`acid (IM) and diethyl ether were added and the layers were
`
`separated. The aqueous layer was extracted with ethyl
`
`acetate. The combined organic layers were dried (MgSO4) and
`the solvent was evaporated. The residue was chromatographed
`
`30
`
`on silica (ethyl acetate—triethylamine 90:10 followed by
`
`methanol)
`
`to afford 3 g containing traces of
`
`triphenylphosphine. The product was used in the next step
`
`without further purification.
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2007 - 1007
`
`Patent Owner, UCB Pharma GmbH – Exhibit 2007 - 1007
`
`

`
`W0 98/43942
`-
`
`35
`
`PCT/SE98/00556
`
`17.3 (R)-N,N-Diisopropy1-3-[2-benzyloxy-5-(6—hydroxyhex-1-
`
`eny1)pheny1]-aéphenylpropanamine
`
`(R)-N,N-Diisopropyl—3-[2-benzyloxy—5-(5—carboxypent-l-
`
`enyl)pheny1]—3—phenylpropanamine was reduced as described
`
`5
`
`in Example 10. Yield 0.35 g (15%).
`
`EXAMPLE 18
`‘
`(R)-N,N-Diisopropy1—3-[5-(2-diisopropy1aminoethy1)-2-
`
`hydroxyphenyll-3-phenylpropanamine hydrochloride
`
`10
`
`(R)-N,N—Diisopropyl-3-[2-benzyloxy—5-(2-
`
`diisopropylaminoethyl)phenyl]—3—phenylpropanamine (0.6 g,
`
`1.13 mmol) was refluxed with concentrated HCl
`
`(25 mL)
`
`overnight. The reaction mixture was then basified with 10 M
`
`sodium hydroxide and extracted with diethyl ether. The
`
`15
`
`organic layer was dried (MgSO4) and concentrated in vacuo
`
`to give 0.5 g oil that was fractionated on a reversed—phase
`
`PEP—RPC HR 30/26 column using a gradient of acetonitrile
`
`(containing 0.1% TFA) and milliQ—water (containing 0.1%
`
`TFA). The pure fractions were pooled and extracted with
`
`20
`
`diethyl ether and 10 M sodium hydroxide. The resulting
`
`diethyl ether solution was treated with hydrogen chloride
`
`in diethyl ether. Yield 50 mg (9%);
`
`[a]D +1.4° (c 0.94,
`
`methanol);
`
`1H NMR (CD3OD) 6 1.27-1.34 (m, 12H), 1.36-1.42
`
`(m, 12H), 2.50-2.58 (m, 1H), 2.60-2.67 (m, 1H), 2.95 (t,
`
`25
`
`2H), 3.05 (m, 2H), 3.15-3.27 (m, 2H), 3.70 (m, 2H), 3.75
`
`(m, 2H), 4.40 (t, 114), 6.80 (d, 1H), 7.02 (dd, 1H), 7.13
`
`(d, 1H), 7.20 (m, 1H), 7.31 (m, 1H), 7.39-7.41 (m, 1H).
`
`Anal.
`
`(C29H45N20'2HCl'0.4H20) C, H, N.
`
`30
`
`The starting compound N,N-diisopropy1—3(R)—[2—
`
`benzyloxy—5-(2—diisopropylaminoethyl)phenyl]-3-
`
`phenylpropanamine was prepared as follows:
`
`18.1 N,N-Diisopropy1-3(R)-(5-formylmethyl-2—benzy1oxy-
`
`35
`
`Iphenyl)-3-phenylpropanamine
`
`DMSO (1.1 mL, 15.5 mmol) dissolved in dichloromethane
`
`was added dropwise to oxalyl chloride (0.64 mL, 7.74 mmol)
`
`at -78 °C under nitrogen atmosphere. After 10 minutes of
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2007 - 1008
`
`Patent Owner, UCB Pharma GmbH – Exhibit 2007 - 1008
`
`

`
`_WO 98/43942
`
`3 6
`
`PCT/SE98I00556
`
`stirring,
`
`(R)—N,N-diisopropyl—3—[2—benzyloxy-5—(2—
`
`hydroxyethyl)phenyl]—3—phenylpropanamine (Example 12.2)
`
`(2.3 g, 5.16 mmol)
`
`in dichloromethane was added and the
`
`-reaction mixture was stirred for additional 1 h.
`
`5
`
`Triethylamine (5.4 mL, 38.7 mmol) was then added and the
`
`temperature was allowed to rise to room temperature. The
`
`reaction mixture was taken up in water and dichloromethane.
`
`The organic layer was dried (MgSO4) and concentrated in
`
`vacuo and the product was used in the next step without
`
`10
`
`further purification.
`
`18.2 (R)-N,N-Diisopropy1-3-[2-benzy1oxy-5-(2-
`
`diisopropylaminoethyl)pheny1J-3-phenylpropanamine
`
`Diisopropylamine (4.2 mL, 30 mmol) was dissolved in
`
`15 methanol
`
`(12 mL). 5 M HCl in methanol
`
`(2 mL) was added
`
`followed by N,N—diisopropyl—3(R)—(5—formylmethyl—2-
`
`benzyloxyphenyl)—3—pheny1propanamine (5 mmol)
`
`in methanol
`
`(10 mL) and sodium cyanoborohydride (0.22 g, 3.5 mmol). The
`
`reaction mixture was stirred at room temperature overnight.
`
`20 methanol was then evaporated, and diethyl ether and H20
`
`were added. The organic layer was dried (MgSO4) and
`
`concentrated in vacuo to give 3 g of a crude product that
`
`was chromatographed on silica (toluene-triethylamine 95:5).
`
`Yield 0.65 g (25%);
`
`1H NMR (CDCI3) 5 0.88-0.91 (m, 18H),
`
`25
`
`1.20 (d, 9H), 2.10-2.20 (m, 2H), 2.30-2.38 (m, 2H), 2.87-
`
`3.10 (m, 4H), 4.34 (m, 1H), 4.98 (d, 2H), 6.75-6.97 (m,
`
`2H), 7.10-7.30 (m, 11H).
`
`EXAMPLE 19
`
`30
`
`(R)-N,N-Diisopropy1-3-(5-ethoxymethyl-2-hydroxyphenyl)-3-
`
`phenylpropanamine
`
`(R)-N,N—Diisopropyl—3—(2-hydroxy-5—hydroxymethyl—
`
`phenyl)—3—phenylpropanamine (prepared as described in W0
`
`(3.9 g, 11.5 mmol) and A1203 (115 g,
`94/11337, Example 1)
`1.13 mol) refluxed in ethyl acetate (0.5 L) for 60 hours.
`
`35
`
`A1203 was filtered offi and ethyl acetate was evaporated.
`Chromatography on silica (toluene—triethylamine, 90:10) of
`
`the residue yielded 2.5 g (59%). The fumarate salt was
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2007 - 1009
`
`Patent Owner, UCB Pharma GmbH – Exhibit 2007 - 1009
`
`

`
`WO 98/43942
`
`PCI‘/SE98/00556
`
`3 7
`
`obtained by adding fumaric acid (0.17 g, 1.48 mmol)
`
`dissolved in warm ethanol to the free base (0.55 g, 1.48
`
`mmol)
`
`in diethyl ether; mp 174-177 °C;
`
`[a]D +5.5° (c 1.02,
`
`methanol);
`
`1H NMR (CD3OD) 0 1.15 (t, 3H), 1.27-1.30 (m,
`
`12H), 2.41-2.49 (m, 1H), 2.52-2.50 (m, 1H), 3.04 (dd, 2H),
`
`3.49 (q, 2H), 3.67 (m, 2H), 4.35 (S, 2H), 4.43 (t, 1H),
`
`6.69 (s, 2H), 6.80 (d, 1H), 7.04 (dd, 1H), 7.12 (d, 1H),
`
`7.18-7.37 (m, 4H). Anal.
`
`(C24H35NO2'C4H4O4) C, H, N.
`
`10
`
`15
`
`20
`
`25
`
`EXAMPLE 2 0
`
`N—Isopropy1-3-(5-carboxy-2-hydroxyphenyl)-3-
`
`phenylpropanamine hydrochloride
`
`N—Benzyl-N—isopropyl-3—(2-benzyloxy-5—carboxyphenyl)—
`
`3—pheny1propanamine (1.3 g, 2.6 mmol) was dissolved in
`
`HOAC. Palladium (10%) on charcoal
`
`(0.13 g) was added and
`
`the mixture was hydrogenated at atmospheric pressure for 48
`
`hours. The catalyst was then filtered off and the solvent
`
`was evaporated. The resulting oil was fractionated on a
`
`reversed—phase PEP—RPC HR 30/26 column using a gradient of
`
`acetonitrile (containing 0.1% TFA) and mi1liQ—water
`
`(containing 0.1% TFA). This purification was done in 16
`
`portions with about 100 mg material each time. The pure
`
`fractions were pooled and freeze-dried to give 0.57 g of
`
`trifluoroacetic acid salt. The crystals were dissolved in 1
`
`M HCl and freeze-dried to give 0.4 g (43%) of the
`
`hydrochloride salt as white crystals; mp 155-160 °C; 1H NM
`
`(DMSO-d5) 5 1.17 (d. 3H), 1.19 (d, 3H), 2.30-2.38 (m, 1H),
`
`2.38-2.46 (m, 1H), 2.72 (br, 1H), 2.80 (br, 1H), 3.25 (m,
`
`1H), 4.40 (t, 1H), 6.94 (d, 1H), 7.18-7.22 (m, 1H). 7.29-
`
`30
`
`7.33 (m, 4H), 7.66 (dd, 1H), 7.76 (d,
`
`lH); Anal.
`
`(C19H23NO3'HCl'0.5H2O) C, H, N.
`
`The starting compound N—benzyl—N—isopropyl—3—(2-
`
`benzyloxy-5-carboxyphenyl)—3—phenylpropanamine was prepared
`as follows:
`
`35
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2007 - 1010
`
`Patent Owner, UCB Pharma GmbH – Exhibit 2007 - 1010
`
`

`
`"W0 98/43942
`
`PCT/SE98/00556
`
`38
`
`20.1 3-(2-Benzyloxy-5—bromopheny1)-3-phenylpropanal
`
`3-(2—Benzyloxy-5—bromophenyl)-3—phenylpropanol
`
`(16.5
`
`g, 41.5 mmol)
`
`(prepared as described in WO 94/11337,
`
`Example lc) was reacted as described in Example 18.1. The
`
`combined organic layers were washed with 2 M HC1,
`
`10%
`
`NaHC03, water and brine, dried (MgSO4) and evaporated to
`
`give 16 g (98%) of yellowish crystals of the product that
`
`was used in the next step without further purification; mp
`
`99-100 0c;
`
`1H mm (CDCl3) 8 3.10 (dd, 2H), 5.0 (s, 2H),
`
`4.98-5.10 (m, 1H), 6.76 (d, 1H), 7.16—7.38 (m, 12H), 9.65
`
`(s, 1H).
`
`20.2 N-Benzy1-N-isopropy1-3-(2-benzyloxy-5-bromophenyl)-3-
`
`phenylpropanamine
`
`To a solution of N—benzylisopropylamine (34 mL, 0.20
`
`mol)
`
`in methanol
`
`(80 mL) was added 5 M HC1 in methanol
`
`(16.2 mL, 80.9 mmol)
`
`followed by 3—(2—benzyloxy-5-
`
`bromophenyl)-3-phenylpropanal
`
`(16.0 g,
`
`40.5 mmol)
`
`in
`
`methanol
`
`(20 mL) and sodium cyanoborohydride (1.78 g, 28.3
`
`mmol). The resulting solution was stirred for 17 hours. The
`
`solvent was evaporated and diethyl ether was added to the
`
`resulting syrup. The solution was washed 3 times with
`
`water,
`
`dried over MgSO4 and evaporated. The residue was
`
`chromatographed on silica (hexane—ethyl acetate, 75:25)
`
`giving 15.9 g of a syrup. The hydrochloride salt of the
`
`compound was prepared by dissolving the product in diethyl
`
`ether and adding HC1 dissolved in diethyl ether. The
`
`resulting oil was washed with diethyl ether, dissolved in
`
`10 M sodium hydroxide and extracted with diethyl ether 3
`
`times. Purification by chromatography on silica (using a
`
`gradient of dichloromethane up to 1% triethylamine in
`
`dichloromethane) yielded 7 g (33%) of the product as a
`
`colourless oil.
`
`1H NMR (CDCl3) 5 0.84 (d, 3H), 0.90 (d,
`
`3H), 2.02-2.12 (m, 2H), 2.38 (t, 2H), 2.90 (m, 1H), 3.50
`
`(d, 2H), 4.50 (t, 1H), 4.95 (S, 2H), 6.70 (s, 1H), 7.10-
`
`7.35 (m, 17H).
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2007 - 1011
`
`Patent Owner, UCB Pharma GmbH – Exhibit 2007 - 1011
`
`

`
`WO 98/43942
`
`39
`
`PCT/SE98/00556
`
`20.3 N—Benzy1-N-isopropy1-3-(2-benzy1oxy-5-carboxyphenyl)-
`
`3-phenylpropanamine
`
`A mixture of magnesium turnings (1.18 g, 48.6 mmol)
`
`and iodine (one small crystal) was warmed gently. A
`
`solution of N—benzyl~N—isopropyl—3—(2—benzyloxy—5-
`
`bromophenyl)-3-phenylpropanamine (6.0 g, 11 mmol) and 1,2-
`
`dibromoethane (0.2 mL, 2.3 mmol)
`
`in dry THF (25 mL) was
`
`added dropwise under nitrogen atmosphere to the refluxing
`
`mixture. After 2 hours of refluxing,
`
`l,2—dibromoethane
`
`10
`
`15
`
`(0.59 mL, 6.8 mmol) was added. The mixture was left
`
`overnight under nitrogen atmosphere. The mixture was then
`
`added together with 1,2-dibromoethane (0.93 mL, 10.8 mmol)
`
`to warmed magnesium turnings
`
`(1.18 g, 48.6 mmol) and iodine
`
`(one small crystal). After 30 minutes of refluxing,
`
`the
`
`mixture was cooled to room temperature and CO2
`
`(g) was
`
`bubbled through. After 3 hours, ammonium chloride (aq, 15%,
`
`50 mL) was added followed by diethyl ether (100 mL). The
`
`layers were separated and the organic layer was dried
`
`(MgSO4) and concentrated to give 5.8 g of an oil. The crude
`product was chromatographed on silica (using a gradient of
`
`20
`
`to give the pure
`acetone up to 5% ethanol in acetone)
`product
`(1.3 g, 23%) as an oil. N-benzyl-N-isopropyl-3-(2-
`
`benzyloxyphenyl)-3-phenylpropanamine (3.1 g) was obtained
`
`as a biproduct from the reaction.
`
`1H NMR (CDCl3) 5 0.98 (d,
`
`3H), 1.10 (d, 3H), 2.30-2.40 (m, 2H), 2.46-2.65 (m, 2H),
`
`3.40 (br, 1H), 3.85 (br, 2H), 4.30 (br, 1H), 4.98 (br, 2H),
`
`6.80 (d, 1H), 7.10-7.40 (m, 15H), 7.95 (d, 1H), 7.95 (d,
`
`1H), 8.20 (s, 1H).
`
`EXAMPLE 21
`
`N-Benzy1-N—isopropy1-3-(2-hydroxypheny1)-3-
`
`phenylpropanamine hydrochloride
`
`N—Benzyl-N-isopropyl-3-(2—benzyloxy—5—carboxyphenyl)—
`
`3-phenylpropanamine, prepared as described in Example 20.3,
`
`(3.1 g, 6.90 mmol) was refluxed in concentrated HCl
`
`(30 mL)
`
`for 20 h. The reaction mixture was allowed to cool to room
`
`temperature and the liquid was poured off. The remaining
`
`oil was washed with water and diethyl ether and then
`
`25
`
`30
`
`35
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2007 - 1012
`
`Patent Owner, UCB Pharma GmbH – Exhibit 2007 - 1012
`
`

`
`’WO 98/43942
`
`PCT/SE98/00556
`
`40
`
`dissolved in 2-propanol. The solution was evaporated and
`
`treated with 10 M sodium hydroxide to give the free base.
`
`Chromatography on silica (hexane:ethyl acetate 75:25)
`
`afforded 0.5 g of the compound that was fractionated on a
`
`reversed—phase PEP—RPC HR 30/26 column using a gradient of
`
`acetonitrile (containing 0.1% TFA) and milliQ-water
`
`(containing 0.1% TFA). The pure fractions were pooled and
`
`extracted with diethyl ether and 10 M sodium hydroxide. To
`
`the resulting diethyl ether solution was added dropwise
`
`10
`
`saturated diethyl ether-HCl
`
`(g). The resulting crystals of
`
`the hydrochloric salt were collected by filtration; mp 115-
`
`122 °C;
`
`1H NMR (DMSO—d5) 5 1.28 (m, 6H), 2.27-2.38 (m, 1H),
`
`2.48-2.55 (m, 1H), 2.72-2.97 (m, 2H), 3.55 (m, 1H), 4.23
`
`(m, 2H), 4.35 (m, 1H), 6.68-6.74 (m, 1H), 6.82 (dt, 1H),
`
`15
`
`6.96-7.24 (m, 7H), 7.38-7.42 (m, 3H), 7.64-7.68 (m, 2H),
`
`9.55 (d, 1H), 10.62 (br,
`
`lH). Anal.
`
`(C25H29NO-HC1) C, H, N.
`
`EXAMPLE 22
`
`20
`
`25
`
`30
`
`(R)-N,N—Diisopropyl—3-[5-(3-aminopropyl)-2-hydroxyphanyll—
`
`3-phenylpropanamine dihydrochloride
`
`(R)-N,N—Diisopropyl—3-[2-benzy1oxy-5-(2-
`
`cyanoethenyl)phenyl]-3-phenylpropanamine (3.20 g, 7.07
`
`mmol) was dissolved in 100 % acetic acid and 10% Pd/C (0.52
`
`g) was added. The mixture was hydrogenated (60 psi)
`
`overnight at room temperature. The catalyst was filtered
`
`off and the solvent was evaporated. The residue was
`
`dissolved in water, basified with sodium hydroxide (11 M),
`extracted with ethyl acetate,
`the organic phase was dried
`
`(MgSO4), and evaporated. The residue was chromatographed on
`
`silica (toluene-ethyl acetate-triethylamine-methanol,
`
`20:5:l.5:1). The amine was redissolved in diethyl ether and
`
`a HCl-saturated diethyl ether solution was carefully added.
`
`The precipitate was filtered off wich gave 0.30 g ( 10 %);
`
`1H NMR (CD30D) 8 1.29 (m, 12H), 1.88 (m, 2H), 2.51(m, 2H),
`
`35-
`
`2.59 (t, 2H), 2.88 (t, 2H), 3.04 (t, 2H), 3.68 (m, 2H),
`
`4.40 (t, 1H), 4.55 (bs, 1H), 6.76 (d, 1H), 6.93 (d, 1H),
`
`7.03 (s, 1H), 7.19 (t, 1H), 7.30 (t, 2H), 7.37 (d, 2H); mp.
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2007 - 1013
`
`Patent Owner, UCB Pharma GmbH – Exhibit 2007 - 1013
`
`

`
`'WO 98/43942
`
`PCT/SE98/00556
`
`41
`
`226-228 °C;
`
`[a]D +11.5° (c=1.0, methanol). Anal.
`
`(C24H35N20*2HCl) C, H, N.
`
`The starting compound (R)—N,N—diisopropyl—3-[2-
`
`benzyloxy—5—(2-cyanoethenyl)pheny1]—3—phenylpropanamine was
`
`prepared as follows:
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`22.1 (R)-N,N-Diisopropy1-3-[2-benzy1oxy-5—(2-cyano-
`
`etheny1)pheny1]-3—pheny1propy1amine
`
`To a solution of
`
`(R)-N,N—diisopropyl—3—(2—benzyloxy-5-
`
`bromophenyl)-3-phenylpropanamine (13.87 g, 28.87 mmol)
`
`(prepared as described in WO 94/11337, Example 1)
`
`in DMF
`
`(140 mL) was added triethylamin (5.00 mL, 36.10 mmol),
`
`Pd(OAc)2 (0.32 g, 1.44 mmol),
`
`tri(o—tolyl)phosphine (1.76
`
`g, 5.77 mmol) and acrylonitrile (2.39 mL, 36.10 mmol). The
`
`reaction mixture was stirred overnight at 115 °C in a
`
`sealed flask equipped with a reflux condenser under
`
`nitrogen atmosphere. The resulting mixture was
`
`concentrated, and the residue was dissolved in diethyl
`
`ether, washed with aqueous 2 M sodium hydroxide and water.
`
`The organic phase was dried (MgSO4) whereafter petroleum
`
`ether was added to the organic phase and a precipitate was
`
`formed. Recrystallisation from ethanol yielded 5.50 g
`
`(42%).
`
`1H NMR (CDC13) 5 0.90 (S, 6H), 0.95 (S, 6H), 2.15
`
`(q, 2H), 2.35 (q, 2H), 2.95 (m, 2H), 4.40 (t, 1H), 5.05 (s,
`
`2H), 5.70 (d, 1H), 6.85 (d, 1H), 7.10-7.50 (m, 13H).
`
`EXAMPLE 23
`
`(R)-N,N-Diisopropy1-3-[5—3-(acetamidopropyl)-2-hydroxy-
`
`phenyll-3-phenylpropanamine hydrochloride
`
`To a solution of
`
`(R)—N,N-diisopropyl-3-[5-(3-
`
`aminopropyl)—2~hydroxyphenyl]-3-phenylpropanamine,
`
`(Example
`
`22),
`
`(0.45 g, 1.23 mmol)
`
`in methanol
`
`(45 mL) was added
`
`acetic anhydride (0.23 mL, 2.47 mmol). The mixture was
`
`stirred for 3 h at room temperature and then evaporated to
`
`dryness. The residue was dissolved in H20, basified with
`
`aqueous 11 M sodium hydroxide and extracted with toluene.
`
`The organic layer was dried with MgSO4, filtered and
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2007 - 1014
`
`Patent Owner, UCB Pharma GmbH – Exhibit 2007 - 1014
`
`

`
`‘WO 98/43942
`-
`
`42
`
`PCT/SE98/00556
`
`evaporated. The amine was dissolved in diethyl ether and a
`
`HC1-saturated diethyl ether solution was carefully added.
`
`The precipitate formed was filtered off to give 0.55 g (100
`
`%).
`
`1H NMR (CD3OD) 5 1.27 (m, 12H), 1.75 (m, 2H), 2.08 (s,
`
`5
`
`3H), 2.52 (m, 4H), 3.04 (t, 2H), 3.20 (t, 2H), 3.68 (m,
`
`2H), 4.40 (t, 2H), 6.72 (d. 1H), 6.90 (d, 1H), 6.99 (5,
`
`1H), 7.19 (t, 1H), 7.30 (m, 4H); mp. 171-175 °C;
`
`[a]D +3.6°
`
`(c=0.5, methanol).
`
`(C25H33N2O2*HCl) C, H, N.
`
`10
`
`EXAMPLE 24
`
`(R)-N,N—Di1sopropyl-3-[5-(2-cyanoethyl)-2—hydroxypheny1]-3-
`
`phenylpropanamine hydrochloride
`
`(R)—N,N—Diisopropyl—3—[2—benzyloxy—5—(2-
`
`cyanoethenyl)phenyl]-3—phenylpropy1amine (Example 22.1),
`
`15
`
`(4.00 g, 8.84 mmol) was treated as described in Example 22,
`
`but the hydrogenation was performed at atmospheric
`
`pressure. Yield 1.35 g (38 %);
`
`1H NMR (CD3OD) 5 1.14 (s,
`
`6H), 1.16 (s, 6H), 2.50 (m, 2H), 2.79 (t, 2H), 3.05 (t,
`
`2H), 3.68 (m, 2H), 4.39 (t, 2H), 6,75 (d, 1H), 6.98 (d,
`1H), 7.09 (s, 1H), 7.19 (t, 1H), 7.32 (m, 4H), mp. 156-159
`
`20
`
`°C;
`
`[a]D +4.0° (c=0.5, methanol); Anal.
`
`(Czfifi2N2O*1.0HCl*0.25H¢O) C, H; N: calcd, 6.9;
`
`found, 6.4.
`
`EXAMPLE 25
`
`25
`
`(R)-N,N—Diisopropy1-3-[S-(2-carbamoylethyl)-2-hydroxy-
`
`phenyll-3-phenylpropanamine hydrochloride.
`
`A solution of
`
`(R)—N,N—diisopropyl-3-[5-(2—cyanoethyl)—
`
`2-hydroxyphenyll-3—pheny1propanamine (Example 24),
`
`(2.00 g,
`
`5.48 mmol),
`
`in conc. HC1 was stirred at 50 °C for 2 h and
`
`30
`
`then evaporated. The residue was dissolved in water,
`
`basified with aqueous 11 M sodium hydroxide and extracted
`
`with toluene. The organic layer was dried (MgSO4),
`
`filtrated and evaporated. The residue was chromatographed
`
`on toluene-ethyl acetate—triethylamine—methanol, 7:2:1:1.
`
`35
`
`The product was obtained from dietyl ether—hydrogen
`
`choride. Yield 0.9 g (39%);
`
`1H NMR (CD3OD)
`
`5 1.31 (m, 12H),
`
`2.44 (t, 2H), 2.53 (m, 2H), 2.78 (t, 2H), 3.04 (t, 2H),
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2007 - 1015
`
`Patent Owner, UCB Pharma GmbH – Exhibit 2007 - 1015
`
`

`
`‘ W0 93/43942
`
`43
`
`PCI‘/SE98/00556
`
`3.67 (m, 2H), 4.39 (t, 1H), 6.72 (d, 1H), 6.82 (d, 1H),
`
`7.02 (S. 1H), 7.18 (t, 1H), 7.32 (m, 4H); mp. 200-202 °C;
`
`[(X]D +7.5° (C=0.5, methanol). Anal.
`
`(C24H34N202*1.0HCl
`
`*0.5H2O) C, H, N.
`
`EXAMPLE 2 6
`
`(R)-N,N-Diisopropyl-3-[5-(2-carboxyethyl)-2-hydroxyphenyll-
`
`3-phenylpropanamine hydrochloride
`
`To'a solution of
`
`(R)-N,N-diisopropyl—3-[5-(2-
`
`10
`
`carbamoylethyl)—2—hydroxyphenyl]-3-phenylpropanamine
`
`(obtained in Example 25),
`
`(0.50 g, 1.31 mmol)
`
`in ethanol
`
`(15 mL) and H¢O (10 mL) was added KOH (3.75 g, 66.8 mmol).
`
`The mixture was stirred overnight at 100 °C. The solvent
`
`was evaporated and the residue redissolved in H20 and
`
`15
`
`washed with diethyl ether. The aqueous layer was acidified
`
`with conc. HCl and the precipitate was collected by
`
`filtration and washed with 2 M Hcl. The product was
`
`fractionated on a reversed—phase PEP RPC HR 30/26
`
`(Pharmacia Biotech AB, Sweden) column using a gradient of
`
`20
`
`20-60% acetonitrile with 0.1% TFA. Fractions were pooled
`and hydrochloric acid (2 mL, conc.) was added and the
`
`solvent was evaporated. The residue was crystallised from
`
`methanol—diethyl ether to give 0.37 g (0.96 mmol, 74%);
`
`1H
`
`NMR (CD3OD) 5 1.28 (m, 12H), 2.48 (m, 4H), 2.76 (t, 2H),
`3.04 (t, 2H), 3.67 (m, 2H), 4.39 (t, 1H), 6.72 (d, 1H),
`
`25
`
`6.92 (d, 1H), 7.00 (s, 1H), 7.19 (t, 1H), 7.32 (m, 4H); mp.
`
`205-207 °C;
`
`[a]D +3.7° (c=l.O, methanol). Anal.
`
`(C24H33NO3*1.0HCl) C, H, N.
`
`30
`
`EXAMPLE 27
`
`(R)-(N,N-Diisopropy1—3-(5-amino-2-hydroxyphenyl)-3-
`
`phenylpropanamine dihydrochloride
`
`(R)—N,N-Diisopropyl-3-(5—azido—2—benzyloxyphenyl)-3-
`
`phenylpropanamine (0.90 g, 2.03 mmol) was dissolved in
`
`35
`
`acetic acid and 10% Pd/C (210 mg, cat.) was added. The
`
`mixture was stirred and exposed to H2
`
`(1 atm.) at room
`
`temperature overnight. The Pd/C catalyst was filtered off,
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2007 - 1016
`
`Patent Owner, UCB Pharma GmbH – Exhibit 2007 - 1016
`
`

`
`W0 98/43942
`
`PCT/SE98/00556
`
`44
`
`and the filtrate evaporated. The residue was dissolved in
`
`water and basified with aqueous 11 M sodium hydroxide,
`
`extracted with diethyl ether, dried (MgS04) filtrated and
`
`evaporated. The crude residue was chromatographed on silica
`
`(n—hexane-ethanol-triethylamine,
`
`7:3:l). The hydrochloride
`
`was obtained from dietyl ether hydrogen chloride. The
`
`resulting oil was freeze—dried from water. Yield 0.30 g (37
`
`as);
`
`1H NMR (DMSO) 8 1.13 — 1.33 (m, 12H), 2.47 (m,
`
`2H).
`
`2.82 (br, 1H), 2.98 (br, 1H), 3.57 (br, 2H),
`
`4.38 (t, 1H),
`
`6.96 (d, 1H), 7.08 (d,
`
`jH), 7.19 (s, 1H),
`
`7.22 (m, 1H),
`
`7.32
`
`(m,
`
`4H), 10.05 (br, 2H), 10.13 (s,
`
`lH); mp. 180-183
`
`°C;
`
`[a]D +21.0° (c=0.1, methanol). Anal.
`
`(C21H3oN2O*2.0HCl*0.5I-I20) C, H, N.
`
`The starting compound (R)—N,N—diisopropyl—3-(5-azido-
`
`2-benzyloxyphenyl)-3-phenylpropanamine was prepared as
`follo