Translated from the German
`Ruth Boggs, MA, CT | ATA-Certified Translator (#62196) & Interpreter | rutheboggs@gmail.com
`Base from HPLC on CSP:
`
`
`Hydrochloridfällung = hydrochloride precipitation
`
`
`
`GRT-NUC00021278_T
`
`HIGHLY CONFIDENTIAL
`For Outside Counsel’s Eyes Only Pursuant to New Jersey Local Patent Rule 2.2
`
`Page 1 of 16
`
`Grunenthal GmbH Exhibit 2018
`Rosellini v. Grunenthal GmbH
`IPR2016-00471
`
`

`
`Translated from the German
`Ruth Boggs, MA, CT | ATA-Certified Translator (#62196) & Interpreter | rutheboggs@gmail.com
`GB-Bu41 I E (BN68)
`Hydrochloride Precipitation
`
`
`
`Technician: M. Mueller Date: Aug. 15, 2002
`
`
`
`
`Project Code: FHWF99 Release code:
`
`
`Hydrochloride precipitation M [g/mol]
`Base HPLC-Fr. II
`251.36
`Methyl ethyl ketone
`
`Water
`
`Trimethylchlorosilane
`
`
`m [g]
`7.60
`
`
`
`
`n [mmol]
`30.34
`
`
`30.24
`
`V [ml]
`
`
`45.14
`0.60
`3.82
`
`
`Apparatus: 100-ml round flask, magnetic stirrer, dropping funnel, thermometer
`
`Patent specification EP 0 693 475 B1:
`
`
`
`The base was released from (1) with dichloromethane/sodium hydroxide solution. After
`drying the solution, dichloromethane was distilled off under vacuum. The racemate was then
`separated on the chiral HPLC column. The resulting enantiomers were reacted with
`trimethylchlorosilane/water in 2-butanone, and the hydrochlorides with a melting point of 150 –
`151 oC were obtained.
`
`Execution:
`
`Dissolve the base in methyl ethyl ketone and mix while stirring first with water and then
`with TMCS dropwise. In doing so, the temperature increases to 41 oC. Stir for 30 minutes.
`No solid precipitates; the solution is clear and colorless.
`
`Remove about half of the solvent on the rotary evaporator. Add 35 ml diethyl ether
`dropwise while stirring. The hydrochloride will separate as oil. Remove the diethyl ether on
`the rotary evaporator; in doing so, the hydrochloride precipitates as a solid. Stir for another
`30 minutes in the ice bath.
`
`Filter by suction; wash the solid thoroughly with diethyl ether and suction dry. Concentrate
`the mother liquor and dry the residue under vacuum. Slurry the remaining solid in diethyl
`ether, filter by suction and suction dry. Combine with the 1st precipitation. = 8.537 g white
`solid.
`
`GB-Bu41 I E x HCl
`
`Solvent: DMSO
`au16.009: GB-Bu41 I E x HCl: OK.
`
`
`
`Flow agent: ethyl acetate / methanol = 3 / 1
`
`Workup:
`
`DC:
`
`1H-NMR:
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`1
`
`GRT-NUC00021279_T
`
`HIGHLY CONFIDENTIAL
`For Outside Counsel’s Eyes Only Pursuant to New Jersey Local Patent Rule 2.2
`
`Page 2 of 16
`
`

`
`Translated from the German
`Ruth Boggs, MA, CT | ATA-Certified Translator (#62196) & Interpreter | rutheboggs@gmail.com
`
`
`
`
`
`
`
`
`
`
`
`
`
`8.70 g hydrochloride
`
`m = 8.537 g (corresponds to 98.1% of theoretical)
`
`white solid
`
`150 – 152 cC
`
`
`
`Theoretical yield:
`
`Yield (raw):
`
`Appearance:
`
`Fusion point:
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`2
`
`GRT-NUC00021280_T
`
`HIGHLY CONFIDENTIAL
`For Outside Counsel’s Eyes Only Pursuant to New Jersey Local Patent Rule 2.2
`
`Page 3 of 16
`
`

`
`Translated from the German
`Ruth Boggs, MA, CT | ATA-Certified Translator (#62196) & Interpreter | rutheboggs@gmail.com
`GB-Bu41 I E (BN68)
`Hydrochloride Precipitation
`
`
`
`
`
`Technician: M. Mueller Date: Oct. 7, 2002
`
`
`
`Project Code: FHWF99 Release code:
`
`
`Hydrochloride precipitation M [g/mol]
`Base HPLC-Fr. II
`251.36
`Methyl ethyl ketone
`
`Water
`
`Trimethylchlorosilane
`
`
`m [g]
`7.60
`
`
`
`
`n [mmol]
`30.24
`
`
`30.24
`
`V [ml]
`
`
`45.14
`0.60
`3.82
`
`
`Apparatus: 100-ml round flask, magnetic stirrer, dropping funnel, thermometer.
`
`Patent specification EP 0 693 475 B1:
`
`
`
`The base was released from (1) with dichloromethane/sodium hydroxide solution. After
`drying the solution, dichloromethane was distilled off under vacuum. The racemate was then
`separated on the chiral HPLC column. The resulting enantiomers were reacted with
`trimethylchlorosilane/water in 2-butanone, and the hydrochlorides with a melting point of 150 –
`151 oC were obtained.
`
`Execution: Dissolve the base in methyl ethyl ketone and mix while stirring first with water and then
`with TMCS dropwise. In doing so, the temperature increases to 41 oC. Remove about half of
`the solvent on the rotary evaporator. Stir for 30 minutes in the ice bath. Add 35 ml diethyl
`ether dropwise and stir for another 90 minutes in the ice bath.
`
`Filter by suction; wash the solid thoroughly with diethyl ether and suction dry. Concentrate
`the mother liquor and dry the residue under vacuum. = 8.07 g white solid. Concentrate the
`mother liquor, slurry the residue in diethyl ether and stir over night at room temperature.
`The residue is oily and will be discarded.
`
`Solvent: DMSO
`dpx022008.003: GB-Bu41 I E x HCl: OK.
`
`Workup:
`
`1H-NMR:
`
`
`Theoretical yield:
`
`Yield (raw):
`
`Appearance:
`
`Fusion point:
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`8.70 g hydrochloride
`
`m = 8.07 g (corresponds to 92.76 % of theoretical)
`
`white solid
`
`148 – 150 cC
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`3
`
`GRT-NUC00021281_T
`
`HIGHLY CONFIDENTIAL
`For Outside Counsel’s Eyes Only Pursuant to New Jersey Local Patent Rule 2.2
`
`Page 4 of 16
`
`

`
`Translated from the German
`Ruth Boggs, MA, CT | ATA-Certified Translator (#62196) & Interpreter | rutheboggs@gmail.com
`GB-Bu347-1-1
`
`
`
`
`Technician: M. Mueller Date: Aug. 19, 2002
`
`Project Code: FHWF99 Release code:
`Batch size:
`M [g/mol] Density Factor n [mmol] m [g] V [ml]
`GB-Bu41 I E x HCl
`287.83
`
`1.0
`29.6
`8.53
`
`Thionyl chloride
`
`
`
`
`8.47
`
`
`
`
`Apparatus:
`500-ml round flask, magnetic stirrer.
`Patent specification EP 0 693 475 B1:
`(+)-(2R,3R)-[3-chloro-3-(-3-methoxy-phenyl)-2-methyl-pentyl)-dimethylamine, hydrochloride (+22)
`
`10 g (35 mmol) (+1), prepared according to Example 2, were mixed with 10 ml thionyl chloride at
`room temperature. To remove excess thionyl chloride, nitrogen was then passed over the reaction mixture
`for 2 hours. After adding another 10 ml thionyl chloride, the reaction mixture was left to stand for 12 hours,
`and then excess thionyl chloride was removed again with the help of a stream of nitrogen over 2.5 hours.
`After drying, the residue was dissolved in 10 ml ice cold 2-butanone and mixed while stirring with 200 ml
`ether and then with 140 ml diisopropyl ether. The supernatant solvent phase was decanted off and the
`remaining oil was again taken up in 10 ml 2-butanone. After adding seed crystals, 300 ml diisopropyl ether
`was added dropwise over 3 hours while stirring vigorously, whereby the hydrochloride crystallized out. 9.8 g
`(91 % of theoretical) (22) were obtained.
`Melting point: 120 oC (decomposition)
`RT = +24.7o (c = 1.01; methanol)
`[α]D
`
`Execution:
`
`Mix Bu41 I E x HCl with thionyl chloride and stir for 1 hour at room temperature. Place under
`nitrogen for 2 hours to remove excess thionyl chloride.
`Add another 8.47 ml thionyl chloride and let stand for 16 hours.
`
`Place again under nitrogen for 2.5 hours while stirring and then dry the residue thoroughly under
`vacuum.
`
`Dissolve the residue in 8.47 ml ice cooled methyl ethyl ketone and add 169 ml diethyl ether and then
`118 ml diisopropyl ether while stirring. Remove the supernatant solvent phase by decanting and take
`up the remaining oil again in 8.47 ml methyl ethyl ketone. Stirring vigorously, add 254 ml diisopropyl
`ether dropwise over 3 hours and continue to stir overnight at room temperature.
`The product is oily. Remove the solvent and dry the residue thoroughly under vacuum.
`Dissolve the remaining green oil in methyl ethyl ketone as described above and add diisopropyl ether
`dropwise over 3 hours. Stir overnight at room temperature.
`The product begins to crystallize. Filter by suction and suction dry in air. The solid is strongly
`hygroscopic; it is removed from the frit with methanol. Remove the solvent and stir the residue
`overnight in diisopropyl ether.
`Completely remove the solvent and dry the residue under vacuum = 8.547g
`Immediately continue reaction into Bu351-1-1.
`
`Workup:
`
`Hydro-
`chloride
`precipi-
`tation:
`
`
`
`Theoretical yield:
`9.076 g hydrochloride
`
`Yield (raw):
`
`m = 8.547 g (corresponds to 94.17 % of theoretical)
`Appearance:
`
`
`
`1
`gray-green solid
`
`
`GRT-NUC00021282_T
`
`HIGHLY CONFIDENTIAL
`For Outside Counsel’s Eyes Only Pursuant to New Jersey Local Patent Rule 2.2
`
`Page 5 of 16
`
`

`
`Translated from the German
`Ruth Boggs, MA, CT | ATA-Certified Translator (#62196) & Interpreter | rutheboggs@gmail.com
`GB-Bu347-1-2
`
`
`
`Technician: M. Mueller Date: Oct. 8, 2002
`
`Project Code: FHWF99 Release code:
`Batch size:
`M [g/mol] Density Factor n [mmol] m [g] V [ml]
`GB-Bu41 I E x HCl
`287.83
`
`1.0
`28.0
`8.07
`
`Thionyl chloride
`
`
`
`
`8.01
`
`
`
`
`Apparatus: 500-ml round flask, magnetic stirrer, ice bath.
`Patent specification EP 0 693 475 B1:
`(+)-(2R,3R)-[3-chloro-3-(-3-methoxy-phenyl)-2-methyl-pentyl)-dimethylamine, hydrochloride (+22)
`
`10 g (35 mmol) (+1), prepared according to Example 2, were mixed with 10 ml thionyl
`chloride at room temperature. To remove excess thionyl chloride, nitrogen was then passed over
`the reaction mixture for 2 hours. After adding another 10 ml thionyl chloride, the reaction mixture
`was left to stand for 12 hours, and then excess thionyl chloride was removed again with the help
`of a stream of nitrogen over 2.5 hours. After drying, the residue was dissolved in 10 ml ice cold 2-
`butanone and mixed while stirring with 200 ml ether and then with 140 ml diisopropyl ether. The
`supernatant solvent phase was decanted off and the remaining oil was again taken up in 10 ml 2-
`butanone. After adding seed crystals, 300 ml diisopropyl ether was added dropwise over 3 hours
`while stirring vigorously, whereby the hydrochloride crystallized out. 9.8 g (91 % of theoretical)
`(22) were obtained.
`Melting point: 120 oC (decomposition)
`RT = +24.7o (c = 1.01; methanol)
`[α]D
`
`Execution:
`
`Mix Bu41 I E x HCl with thionyl chloride and stir for 1 hour at room temperature. Place
`under nitrogen for 2 hours to remove excess thionyl chloride.
`Add another 8.0 ml thionyl chloride and let stand for 16 hours.
`
`Place again under nitrogen for 2.5 hours while stirring and then dry the residue
`thoroughly under vacuum.
`
`Dissolve the residue in 8.0 ml ice cooled methyl ethyl ketone and add 159.6 ml diethyl
`ether and then 111.5 ml diisopropyl ether while stirring. Remove the supernatant solvent
`phase by decanting and take up the remaining oil again in 8.0 ml ice cooled methyl
`ethyl ketone. Stirring vigorously, add 240 ml diisopropyl ether dropwise over 3 hours.
`The hydrochloride does not crystallize out; the product is oily.
`Remove the solvent and dry the residue thoroughly under vacuum. = 7.4 g dark green
`oil.
`Immediately continue reaction into Bu351-1-1.
`
`Workup:
`
`Hydrochloride
`precipitation:
`
`
`Theoretical yield:
`Yield (raw):
`
`Appearance:
`
`
`
`
`
`
`
`
`
`
`8.59 g hydrochloride
`m = 7.4 g (corresponds to 86.15 % of theoretical)
`dark green oil
`
`
`
`
`
`
`
`
`
`
`
`
`
`2
`
`GRT-NUC00021283_T
`
`HIGHLY CONFIDENTIAL
`For Outside Counsel’s Eyes Only Pursuant to New Jersey Local Patent Rule 2.2
`
`Page 6 of 16
`
`

`
`Translated from the German
`Ruth Boggs, MA, CT | ATA-Certified Translator (#62196) & Interpreter | rutheboggs@gmail.com
`GB-Bu347-1-3
`
`
`
`Project Code: FHWF99 Release code:
`Technician: M. Mueller Date: Oct. 30, 2002
`Batch size:
`M [g/mol] Density Factor n [mmol] m [g] V [ml]
`GB-Bu41 I E x HCl
`287.83
`
`1.0
`31.6
`9.08
`
`Thionyl chloride
`
`
`
`
`9.02
`
`
`
`
`Apparatus: 500-ml round flask, magnetic stirrer.
`Patent specification EP 0 693 475 B1:
`(+)-(2R,3R)-[3-chloro-3-(-3-methoxy-phenyl)-2-methyl-pentyl)-dimethylamine, hydrochloride (+22)
`
`10 g (35 mmol) (+1), prepared according to Example 2, were mixed with 10 ml thionyl chloride at
`room temperature. To remove excess thionyl chloride, nitrogen was then passed over the reaction mixture
`for 2 hours. After adding another 10 ml thionyl chloride, the reaction mixture was left to stand for 12 hours,
`and then excess thionyl chloride was removed again with the help of a stream of nitrogen over 2.5 hours.
`After drying, the residue was dissolved in 10 ml ice cold 2-butanone and mixed while stirring with 200 ml
`ether and then with 140 ml diisopropyl ether. The supernatant solvent phase was decanted off and the
`remaining oil was again taken up in 10 ml 2-butanone. After adding seed crystals, 300 ml diisopropyl ether
`was added dropwise over 3 hours while stirring vigorously, whereby the hydrochloride crystallized out. 9.8 g
`(91 % of theoretical) (22) were obtained.
`Melting point: 120 oC (decomposition)
`RT = +24.7o (c = 1.01; methanol)
`[α]D
`
`Execution: Mix Bu41 I E x HCl with thionyl chloride and stir for 1 hour at room temperature. Place under nitrogen
`for 2 hours to remove excess thionyl chloride.
`Add another 8.47 ml thionyl chloride and let stand for 16 hours.
`
`Place again under nitrogen for 2.5 hours while stirring and then dry the residue under vacuum.
`
`Stir the residue in 200 ml diethyl ether and then decant off the supernatant. Take up the oil again in 200
`ml diethyl ether and store overnight in the refrigerator.
`Remove the solvent and dry the oily residue under vacuum (0.5 mbar).
`Stir the oil in approx. 300 ml diethyl ether and decant off. Dissolve the residue in 15 ml methyl ethyl
`ketone and while stirring and cooling in an ice bath add 180 ml diethyl ether and then 270 ml
`diisopropyl ether dropwise, and continue to stir overnight at room temperature.
`Filter by suction; wash the solid with diethyl ether and suction dry on air.
`Scratch up the residue remaining in the flask and stir in diethyl ether.
`Filter by suction again and wash and suction dry as before. The solid is strongly hygroscopic; remove it
`from the frit with methanol, remove the solvent, and dry the residue under vacuum. Mix the residue with
`diisopropyl ether while stirring vigorously and continue to stir overnight at room temperature.
`
`The product begins to crystallize. Completely remove the solvent and dry the residue under vacuum.
`= 9.5 g gray-green solid.
`
`Workup:
`
`Hydro-
`chloride
`precipi-
`tation:
`
`
`Theoretical yield:
`Yield (raw):
`
`Appearance:
`
`
`
`
`
`
`
`
`
`
`9.076 g hydrochloride
`m = 9.5 g (corresponds to >100% of theoretical)
`gray-green solid
`
`
`
`
`
`
`
`
`
`
`
`
`
`3
`
`GRT-NUC00021284_T
`
`HIGHLY CONFIDENTIAL
`For Outside Counsel’s Eyes Only Pursuant to New Jersey Local Patent Rule 2.2
`
`Page 7 of 16
`
`

`
`Translated from the German
`Ruth Boggs, MA, CT | ATA-Certified Translator (#62196) & Interpreter | rutheboggs@gmail.com
`GB-Bu351-1-1 (BN243)
`
`
`
`Project Code: FHW F99 Release code:
`Technician: M. Mueller Date: Aug. 22, 2002
`Batch size:
`M [g/mol] Density Factor n [mmol] m [g] V [ml]
`GB-Bu347-1-1 x HCl
`306.27
`
`1.0
`27.9
`8.55
`
`Diethyl ether, dried
`
`
`
` 174.42
`Zn(BH4)-solution
`
`
`
` 436.04
`Triphenylphosphine
`
`
`
`6.54
`
`
`
`
`
`
`
`Apparatus: 4000-ml three-neck flask, 1000-ml three-neck flask, magnetic stirrer, N2, drying tube, ice bath.
`Patent specification EP 0 693 475 B1:
`(+)-(2R,3R)-[3-(-3-methoxy-phenyl)-2-methyl-pentyl)-dimethylamine, hydrochloride (+23)
`
`46 g dried zinc chloride were dissolved in 580 ml dry ether and then added dropwise to a slurry of 31g
`sodium borohydride in 1800 ml ether. After stirring for 12 hours, 500 ml were decanted from the resulting
`zinc borohydride suspension and added dropwise to 9.8 g (32 mmol) (+22) in 200 ml dry ether. The reaction
`mixture was stirred at room temperature for 72 hours and then cooled in the ice bath and mixed dropwise
`with 40 ml of a saturated ammonium chloride solution. After phase separation, the ether phase was washed
`twice with saturated salt solution and after drying over sodium sulfate, the solvent was distilled off under
`vacuum. 7.3 g of an amine-borane complex were obtained, which was dissolved in 100 ml dry methanol to
`isolate the free base. After adding 7.5 g triphenylphosphine, the mixture was heated and refluxed for 18
`hours. After the solvent was removed by distillation, the residue was mixed with 100 ml 5%-hydrochloric
`acid, and the hydrochloric acid phase was then washed two more times with 50 ml ether. Then the
`hydrochloric acid phase was rendered alkaline with concentrated sodium hydroxide solution while cooling in
`the ice bath, and extracted by shaking twice with 50 ml dichloromethane each. After drying the combined
`organic phases over sodium sulfate, the solvent was distilled off under vacuum and the remaining residue
`(5.2 g) was taken up in 2-butanone. After adding trimethylchlorosilane/water, 4.3 g (50 % of theoretical) of
`hydrochloride (+23) crystallized out.
`Melting point: 163 - 164 oC
`RT = +25.2o (c = 0.95, methanol)
`[α]D
`
`Execution: Zinc chloride is strongly hygroscopic. It is dried at 70 oC and under vacuum over night in the
`drying pistol.
`46 g dried zinc chloride are dissolved in 580 ml dried diethyl ether and filtered over sodium
`sulfate.
`
`Step 1: Suspend 31 g sodium borohydride in 1800 ml dried diethyl ether and mix dropwise
`while stirring and under N2 with the zinc chloride solution. Stir for 3 days at room
`temperature.
`
`Remove 436 ml from the resulting zinc borohydride suspension by decanting.
`
`Step 2: Suspend Bu347 in dried diethyl ether and mix dropwise while stirring and under N2
`with 436 ml zinc borohydride solution. Stir for 5 days.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`1
`
`GRT-NUC00021285_T
`
`HIGHLY CONFIDENTIAL
`For Outside Counsel’s Eyes Only Pursuant to New Jersey Local Patent Rule 2.2
`
`Page 8 of 16
`
`

`
`Translated from the German
`Ruth Boggs, MA, CT | ATA-Certified Translator (#62196) & Interpreter | rutheboggs@gmail.com
`
`Workup: While cooling with ice, add 34.9 ml saturated ammonium chloride solution dropwise.
`Separate the phases. Wash the ether phase twice with saturated NaCl solution, filter over
`sodium sulfate, concentrate and dry under vacuum. 5.7 g of an amine-borane complex are
`obtained.
`
`Dissolve the amine-borane complex in 78 ml dried methanol, mix with 5.86 g
`triphenylphosphine and stir for 18 hours while refluxing.
`Remove the solvent on the rotary evaporator and mix the residue with 78 ml 5%-
`hydrochloric acid. Wash the hydrochloric acid phase twice with 39 ml each diethyl ether.
`Then render the hydrochloric acid phase alkaline (pH9) with 6N NaOH while cooling with
`ice and extract twice with 39 ml each dichloromethane. Filter the extract over sodium
`sulfate; concentrate and dry under vacuum. = 3.94 g base.
`
`Dissolve 3.94 g (corresponds to 16.75 mmol) base in 25 ml methyl ethyl ketone. While
`stirring, first add 0.33 ml water and then 2.12 ml (corresponds to 16.75 mmol) TMCS and
`stir in the ice bath. After 15 minutes, the hydrochloride was obtained as a white solid. Add
`25 ml diethyl ether and filter by suction; wash the solid thoroughly with diethyl ether and
`suction dry for 1 hour = 4.234 g white hydrochloride; fusion point = 152 – 154 oC
`Concentrate the mother liquor and dry the residue under vacuum. = 0.311 g white
`hydrochloride.
`
`GB-Bu351-1-1-1
`
`Solvent: DMSO
`DPX020902.001: GB-Bu351-1-1-3 Hydrochloride: OK
`
`GB-Bu351-1-1-4 hydrochloride: -23.4o (c = 0.955 % in methanol)
`
`Releasing
`the base:
`
`Hydro-
`chloride
`precipi-
`tation:
`
`
`DC:
`
`1H-NMR:
`
`
`Amount of
`rotation:
`
`
`Flow agent: ethyl acetate / methanol = 1 / 1
`
`
`
`
`
`
`
`
`
`
`7.59 g hydrochloride
`m = 4.545 g (corresponds to 59.88 % of theoretical)
`white solid
`152 – 154 oC
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`2
`
`Theoretical yield:
`Yield (raw):
`
`Appearance:
`
`Fusion point:
`
`
`
`
`
`
`
`
`GRT-NUC00021286_T
`
`HIGHLY CONFIDENTIAL
`For Outside Counsel’s Eyes Only Pursuant to New Jersey Local Patent Rule 2.2
`
`Page 9 of 16
`
`

`
`Translated from the German
`Ruth Boggs, MA, CT | ATA-Certified Translator (#62196) & Interpreter | rutheboggs@gmail.com
`GB-Bu351-1-2 (BN243)
`
`
`Technician: M. Mueller Date: Oct. 8, 2002
`
`Project Code: FHW F99 Release code:
`Batch size:
`M [g/mol] Density Factor n [mmol] m [g] V [ml]
`GB-Bu347-1-1 x HCl
`306.27
`
`1.0
`24.2
`7.40
`
`Diethyl ether, dried
`
`
`
` 151.01
`Zn(BH4)-solution
`
`
`
` 377.53
`Triphenylphosphine
`
`
`
`5.66
`
`
`
`
`
`
`
`
`
`Apparatus: 4000-ml three-neck flask, 1000-ml three-neck flask, magnetic stirrer, N2, drying tube, ice bath.
`Patent specification EP 0 693 475 B1:
`(+)-(2R,3R)-[3-(-3-methoxy-phenyl)-2-methyl-pentyl)-dimethylamine, hydrochloride (+23)
`
`46 g dried zinc chloride were dissolved in 580 ml dry ether and then added dropwise to a slurry of
`31 g sodium borohydride in 1800 ml ether. After stirring for 12 hours, 500 ml were decanted from the
`resulting zinc borohydride suspension and added dropwise to 9.8 g (32 mmol) (+22) in 200 ml dry ether. The
`reaction mixture was stirred at room temperature for 72 hours and then cooled in the ice bath and mixed
`dropwise with 40 ml of a saturated ammonium chloride solution. After phase separation, the ether phase
`was washed twice with saturated salt solution, and after drying over sodium sulfate, the solvent was distilled
`off under vacuum. 7.3 g of an amine-borane complex were obtained, which was dissolved in 100 ml dry
`methanol to isolate the free base. After adding 7.5 g triphenylphosphine, the mixture was heated and
`refluxed for 18 hours. After the solvent was removed by distillation, the residue was mixed with 100 ml 5%-
`hydrochloric acid, and the hydrochloric acid phase was then washed two more times with 50 ml ether. Then
`the hydrochloric acid phase was rendered alkaline with concentrated sodium hydroxide solution while
`cooling in the ice bath, and extracted by shaking twice with 50 ml dichloromethane each. After drying the
`combined organic phases over sodium sulfate, the solvent was distilled off under vacuum and the remaining
`residue (5.2 g) was taken up in 2-butanone. After adding trimethylchlorosilane/water, 4.3 g (50% of
`theoretical) of hydrochloride (+23) crystallized out.
`Melting point: 163 - 164 oC
`RT = +25.2o (c = 0.95, methanol)
`[α]D
`
`Execution:
`
`Zinc chloride is strongly hygroscopic. It is dried at 70 oC and under vacuum over night in the drying
`pistol.
`46 g dried zinc chloride are dissolved in 580 ml dried diethyl ether and filtered over sodium sulfate.
`
`Step 1: Suspend 31 g sodium borohydride in 1800 ml dried diethyl ether and mix dropwise while
`stirring and under N2 with the zinc chloride solution. Stir for 20 hours at room temperature.
`
`Remove 377.5 ml from the resulting zinc borohydride suspension by decanting.
`
`Step 2: Stir Bu347 x HCl in 151 ml dried diethyl ether and mix dropwise while stirring and under N2
`with 377.5 ml zinc borohydride solution. Stir for 72 hours.
`
`Workup: While cooling with ice, add 30.2 ml saturated ammonium chloride solution dropwise.
`Separate the phases. Wash the ether phase twice with saturated NaCl solution, filter over
`sodium
`
`
`
`
`
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`
`
`
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`
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`
`
`
`
`3
`
`
`
`GRT-NUC00021287_T
`
`HIGHLY CONFIDENTIAL
`For Outside Counsel’s Eyes Only Pursuant to New Jersey Local Patent Rule 2.2
`
`Page 10 of 16
`
`

`
`Translated from the German
`Ruth Boggs, MA, CT | ATA-Certified Translator (#62196) & Interpreter | rutheboggs@gmail.com
`
`
`
`Releasing
`the base:
`
`Hydro-
`chloride
`precipi-
`tation:
`
`
`DC:
`
`1H-NMR:
`
`
`
`
`sulfate, concentrate and dry under vacuum. 0.115 g of an amine-borane complex is obtained.
`Adjust the aqueous phase (pH = 1) to pH8 with 6N NaOH and extract twice with diethyl
`ether. Filter the extract over sodium sulfate; combine with the first extract, concentrate and
`dry under vacuum. = 4.025 g dark brown oil.
`
`
`
`
`3
`Dissolve the oil in 55 ml dried methanol, mix with 4.14 g triphenylphosphine and stir for 18
`hours while refluxing.
`
`
`
`
`Remove the solvent on the rotary evaporator and mix the residue with 55 ml 5%-
`hydrochloric acid. Wash the hydrochloric acid phase twice with 100 ml each diethyl ether.
`Then render the hydrochloric acid phase alkaline (pH9) with 6N NaOH while cooling with
`ice and extract twice with 50 ml each dichloromethane. Filter the extract over sodium
`sulfate; concentrate and dry under vacuum. = 3.559 g base.
`
`Dissolve 3.559 g (corresponds to 15.13 mmol) base in 22.5 ml methyl ethyl ketone. While
`stirring, first add 0.30 ml water and then 1.91 ml (corresponds to 15.13 mmol) TMCS and
`stir in the ice bath. After 15 minutes, the hydrochloride is obtained as a white solid. Add 25
`ml diethyl ether and stir for another 15 minutes.
`Filter by suction; wash the solid thoroughly with diethyl ether and suction dry overnight.
`3.761 g hydrochloride are obtained; fusion point = 146 – 148 oC
`Concentrate the mother liquor and dry the residue under vacuum. = 0.475 g
`
`GB-Bu351-1-2-1
`
`Solvent: DMSO
`021017.002: GB-Bu351-1-2-2: no product (it is possible that Bu346 was obtained)
`
`
`Flow agent: ethyl acetate / methanol = 1 / 1
`
`
`
`
`
`
`
`
`7.59 g hydrochloride
`
`
`
`./.
`
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`
`
`
`
`
`4
`
`
`
`Theoretical yield:
`
`Yield (raw):
`
`
`
`
`
`
`
`
`
`
`
`
`
`GRT-NUC00021288_T
`
`HIGHLY CONFIDENTIAL
`For Outside Counsel’s Eyes Only Pursuant to New Jersey Local Patent Rule 2.2
`
`Page 11 of 16
`
`

`
`Translated from the German
`Ruth Boggs, MA, CT | ATA-Certified Translator (#62196) & Interpreter | rutheboggs@gmail.com
`
`GB-Bu351-1-3 (BN243)
`
`
`
`
`
`
`Technician: M. Mueller Date: Nov. 6, 2002
`
`Project Code: FHW F99 Release code:
`Batch size:
`M [g/mol] Density Factor n [mmol] m [g] V [ml]
`GB-Bu347-1-1 x HCl
`306.27
`
`1.0
`29.4
`9.00
`
`Diethyl ether, dried
`
`
`
` 183.66
`Zn(BH4)-solution
`
`
`
` 459.15
`Triphenylphosphine
`
`
`
`6.89
`
`
`
`
`
`
`
`Apparatus: 4000-ml three-neck flask, 1000-ml three-neck flask, magnetic stirrer, N2, drying tube, ice bath.
`Patent specification EP 0 693 475 B1:
`(+)-(2R,3R)-[3-(-3-methoxy-phenyl)-2-methyl-pentyl)-dimethylamine, hydrochloride (+23)
`
`46 g dried zinc chloride were dissolved in 580 ml dry ether and then added dropwise to a slurry of
`31 g sodium borohydride in 1800 ml ether. After stirring for 12 hours, 500 ml were decanted from the
`resulting zinc borohydride suspension and added dropwise to 9.8 g (32 mmol) (+22) in 200 ml dry ether. The
`reaction mixture was stirred at room temperature for 72 hours and then cooled in the ice bath and mixed
`dropwise with 40 ml of a saturated ammonium chloride solution. After phase separation, the ether phase
`was washed twice with saturated salt solution, and after drying over sodium sulfate, the solvent was distilled
`off under vacuum. 7.3 g of an amine-borane complex were obtained, which was dissolved in 100 ml dry
`methanol to isolate the free base. After adding 7.5 g triphenylphosphine, the mixture was heated and
`refluxed for 18 hours. After the solvent was removed by distillation, the residue was mixed with 100 ml 5%-
`hydrochloric acid, and the hydrochloric acid phase was then washed two more times with 50 ml ether. Then
`the hydrochloric acid phase was rendered alkaline with concentrated sodium hydroxide solution while
`cooling in the ice bath, and extracted by shaking twice with 50 ml dichloromethane each. After drying the
`combined organic phases over sodium sulfate, the solvent was distilled off under vacuum and the remaining
`residue (5.2 g) was taken up in 2-butanone. After adding trimethylchlorosilane/water, 4.3 g (50% of
`theoretical) of hydrochloride (+23) crystallized out.
`Melting point: 163 - 164 oC
`RT = +25.2o (c = 0.95, methanol)
`[α]D
`
`Execution:
`
`Zinc chloride is strongly hygroscopic. It is dried at 70 oC and under vacuum overnight in the drying
`pistol.
`48.3 g dried zinc chloride are dissolved in 600 ml dried diethyl ether and filtered over sodium sulfate.
`
`Step 1: Suspend 32.5 g sodium borohydride in 1700 ml dried diethyl ether and mix dropwise while
`stirring and under N2 with the zinc chloride solution. Stir for 5 days at room temperature.
`
`Remove 460 ml from the resulting zinc borohydride suspension by decanting.
`
`Step 2: Suspend Bu347 in dried diethyl ether and mix dropwise while stirring and under N2 with 460
`ml zinc borohydride solution. Stir for 3 days.
`
`
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`5
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`GRT-NUC00021289_T
`
`HIGHLY CONFIDENTIAL
`For Outside Counsel’s Eyes Only Pursuant to New Jersey Local Patent Rule 2.2
`
`Page 12 of 16
`
`

`
`Translated from the German
`Ruth Boggs, MA, CT | ATA-Certified Translator (#62196) & Interpreter | rutheboggs@gmail.com
`
`
`Workup: While cooling with ice, add 36.6 ml saturated ammonium chloride solution dropwise.
`This results in a strong emulsion. Filter the reaction mixture by suction through a frit and
`wash the gel-like residue twice with 50 ml each diethyl ether. Separate the phases from the
`filtrate. Wash the aqueous phase once with 200 ml diethyl ether. Wash the ether phase twice
`with 25 ml each saturated NaCl solution, filter over sodium sulfate, concentrate and dry
`under vacuum. 7.1 g of an amine-borane complex are obtained.
`
`Dissolve the amine-borane complex in 97 ml dried methanol, mix with 7.3 g
`triphenylphosphine and stir for 18 hours while refluxing.
`Remove the solvent on the rotary evaporator and mix the residue with 97 ml 5%-
`hydrochloric acid. Wash the hydrochloric acid phase twice with 50 ml each diethyl ether.
`Then render the hydrochloric acid phase alkaline (pH9) with 6N NaOH while cooling with
`ice and extract twice with 50 ml each dichloromethane. Filter the extract over sodium
`sulfate, concentrate and dry under vacuum. = 4.343 g base.
`
`Dissolve 4.343 g (corresponds to 18.46 mmol) base in 28 ml methyl ethyl ketone. While
`stirring, first add 0.36 ml water and then 2.34 ml (corresponds to 18.46 mmol) TMCS and
`stir in the ice bath. After 10 minutes, the hydrochloride was obtained as a white solid. Add
`25 ml diethyl ether and filter by suction; wash the solid thoroughly with diethyl ether and
`suction dry for 1 hour = 4.326 g white hydrochloride.
`Concentrate the mother liquor and dry the residue under vacuum. = 0.733 g white
`hydrochloride.
`
`GB-Bu351-1-3-1
`
`Solvent: DMSO
`021118.005: GB-Bu351-1-3-2 HCl: OK.
`
`GB-Bu351-1-3-3 HCl: -22.7o, (c = 1.087 % in methanol)
`
`Releasing
`the base:
`
`Hydro-
`chloride
`precipi-
`tation:
`
`
`DC:
`
`1H-NMR:
`
`Amount of
`rotation:
`
`
`Flow agent: ethyl acetate / methanol = 1 / 1
`
`7.99 g hydrochloride
`
`
`
`m = 5.059 (corresponds to 63.32 % of theoretical)
`
`white solid
`
`156-158 oC
`
`
`Theoretical yield:
`
`Yield (raw):
`
`Appearance:
`
`Fusion point:
`
`
`
`
`
`
`
`
`
`
`
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`
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`
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`6
`
`GRT-NUC00021290_T
`
`HIGHLY CONFIDENTIAL
`For Outside Counsel’s Eyes Only Pursuant to New Jersey Local Patent Rule 2.2
`
`Page 13 of 16
`
`

`
`Translated from the German
`Ruth Boggs, MA, CT | ATA-Certified Translator (#62196) & Interpreter | rutheboggs@gmail.com
`GB-Bu322-1-1 (BN200)
`
`
`
`
`Technician: M. Mueller Date: Sept. 5, 2002
`
`Project Code: FHWF99 Release code:
`Batch size:
`M [g/mol] Density Factor n [mmol] m [g] V [ml]
`GB-Bu351-1-1 x HCl
`271.83
`
`1.0
`16.7
`4.55
`
`Aqueous HBr
`
`
`
` 111.47
`
`
`
`
`Apparatus: 250-ml round flask, oil bath, sniffing line.
`Patent specification EP 0 693 475 B1:
`(+)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol, hydrochloride (+21)
`
`
`4.3 g (15 mmol) (+23) from Step 2 were mixed with 100 ml concentrated hydrobromic acid. Then
`the mixture was heated for 2 hours while refluxing. After cooling to room temperature, the reaction mixture
`was concentrated using a water stream vacuum. The residue was mixed with concentrated sodium
`hydrogen carbonate solution until alkaline. After extracting twice with 50 ml each dichloromethane, the
`combined organic phases were dried over sodium sulfate. Then dichloromethane was distilled off under
`vacuum and the residue (4 g) was taken up in 2-butanone. After adding trimethylchlorosilane/water, 3.8 g
`(98% of theoretical) of hydrochloride (+21) crystallized out.
`Melting point: 194 - 196 oC
`RT = +24.5 (c = 1.10, methanol)
`[α]D
`
`Execution:
`
`Mix Bu351 with HBr and stir for 2 hours while refluxing.
`
`Let cool. Concentrate under vacuum. Render the residue alkaline with concentrated sodium
`hydrogen carbonate solution. Extract twice with 50 ml each dichloromethane. Filter the extract over
`sodium sulfate, concentrate and dry under vacuum. = 2.147 g base.
`
`Dissolve 2.147 g (corresponds to 10.92 mmol) base in 16.4 ml methyl ethyl ketone. Mix first with
`0.22 ml water and then with 1.38 ml TMCS. Stir for 90 minutes in the ice bath.
`Filter by suction; wash thoroughly with methyl ethyl ketone and suction dry. = 1.647 hydrochloride.
`
`
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`
`
`GRT-NUC00021291_T
`
`HIGHLY CONFIDENTIAL
`For Outside Counsel’s Eyes Only Pursuant to New Jersey Local Patent Rule 2.2
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`1
`
`
`
`Solvent: DMSO
`dpx020909.0