Translated from the German
`Ruth Boggs, MA, CT | ATA-Certified Translator (#62196) for German <> English | rutheboggs@gmail.com
`
`Project Number: AHW
`Notebook: Substance provision
`Creation Date: 2009.12.02
`Modify Date: 2009.12.09
`
`Notebook Entry
`
`
`
`Mueller, Marita
`CG5503
`PG1026-001
`Methoxy Cleavage
`Grünenthal GmbH
`GPR-TD-PD
`
`
`
` -
`
` according to patent specification EP 0 693 475 B1
`and/or reaction specification for GB-Bu322-1-3
`
`
`Planned Amounts
`
`Actual Amounts
`
`Equiv Mass
`
`Volume Moles
`
`Equiv
`
`
`PG1026
`257.80
`C14H24CINO
`
`Bu351,HBr-salt
`316.28
`C15H26BrNO
`
`Name
`MW
`MF
`
`
`
`Materials
`
`Class
`
`Name
`
`Lot Number equiv
`
`g
`
`mL
`
`mmoles equiv
`
`Reactants Bu351,HBr-salt [LR]
`
`47% Hydrobromic acid, in water
`Sodiumhydrogencarbonate solution, saturated in water
`
`*
`
`Chemicals
`
`Dichloromethane, canned product
`
`Methylethylketone, canned product
`
`Trimethylchlorosilane
`
`Deionized water
`
`PG1026
`
`Products
`
`
`
`
`
`
`
`
`
`
`
`
`1.00
`n/a
`n/a
`
`n/a
`
`n/a
`
`n/a
`
`n/a
`
`1.00
`
`5.00
`15.81
`5.00
`150.00 100.00 871.32
`n/a
`n/a
`n/a
`
`1.00
`n/a
`n/a
`
`132.50 100.00 1560.07 n/a
`
`14.09
`
`17.50
`
`195.42
`
`1.28
`
`0.24
`
`4.08
`
`1.49
`0.24
`
`n/a
`
`11.78
`
`13.04
`
`15.81
`
`n/a
`
`n/a
`
`n/a
`
`0.64
`
`HIGHLY CONFIDENTIAL
`
`
`GRT-NUC00056648_T
`
`Page 1 of 12
`
`Grunenthal GmbH Exhibit 2031
`Rosellini v. Grunenthal GmbH
`IPR2016-00471
`
`

`
`
`Translated from the German
`Ruth Boggs, MA, CT | ATA-Certified Translator (#62196) for German <> English | rutheboggs@gmail.com
`
`
`Materials
`
`Class
`
`Name
`
`Actual Amounts
`
`Properties
`
`Mass Volume Moles
`
`Strength
`
`Density MW
`
`g
`
`mL
`
`mmoles
`
`n/a
`
`g/mL
`
`n/a
`
`Reactants Bu351,HBr-salt [LR]
`
`5.00
`
`5.00
`
`15.81
`
`3.16 M
`
`47% hydrobromic acid, in water
`
`150.00 100.00
`
`871.32
`
`8.71 M
`
`Sodiumhydrogencarbonate solution, saturated in water n/a
`
`n/a
`
`n/a
`
`11.90 M
`
`Dichloromethane, canned product
`
`132.50 100.00
`
`1560.07
`
`15.60 M
`
`Chemicals
`
`1.00
`
`1.50
`
`1.00
`
`1.32
`
`0.81
`
`0.86
`
`1.00
`
`316.28
`
`80.91
`
`84.01
`
`84.93
`
`72.11
`
`108.64
`
`18.02
`
`n/a
`
`n/a
`
`n/a
`
`2.60
`
`n/a
`
`n/a
`
`n/a
`
`n/a
`
`n/a
`
`n/a
`
`n/a
`
`11.17 M
`
`7.91 M
`
`55.51 M
`
`10.09
`
`100.00 wt/wt% 1.00
`
`257.80
`
`Methylethylketone, canned product
`
`Trimethylchlorosilane
`
`Deionized water
`
`Products
`
`PG1026
`
`
`
`Identity
`
`PG1026, C14H24CINO,
`257.80 (calculated)
`
`Theoretical Yield (corrected for
`product strength)
`
`Actual Yield
`
`1.00 equiv; 15.81 mmoles; 4.08
`g (Based on Planned)
`1.00 equiv; 15.81 mmoles; 4.08
`g (Based on Actuals)
`
`63.80%
`0.64 equiv; 10.09 mmoles; 2.60
`g (Based on Actuals)
`
`Meta
`Data
`
`
`Process Mass
`Intensity Review
`74.37 (Based on
`Theoretical)
`110.58 (Based on
`Actuals)
`
`Patent specification EP 0 693 475 B1:
`[Image 1]
`(+)-(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 two 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 dichloromethane each, 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
`
`HIGHLY CONFIDENTIAL
`
`
`GRT-NUC00056649_T
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`Page 2 of 12
`
`

`
`
`Translated from the German
`Ruth Boggs, MA, CT | ATA-Certified Translator (#62196) for German <> English | rutheboggs@gmail.com
`
`
`
`November 12, 2009
`
` *
`
` 4.3g Bu351-HCI-salt corresponds to 5.0g Bu351-HBr-salt
`
`250ml round flask, magnetic stirrer, oil bath, reflux cooler
`
`
`Apparatus:
`
`Execution:
`- preheat oil bath to 130 oC
`- mix Bu351, HBr-salt (5 g [Limiting Reagent]; 1.00 equiv; 15.81 mmoles; 5.00 mL; 5.00 g; [Actual]) with 47 %-hydrobromic acid in water (100 mL; 871.32
`mmoles; 100.00 mL;150.00 g; [Actual])
`- reflux for 2 hours while stirring
`
`Workup:
`- remove the oil bath and allow to cool a bit
`- concentrate on the rotary evaporator
`- pour the residue into a 500ml-Erlenmeyer flask and slowly (Warning: strong development of gases) alkalize with saturated sodium hydrogen carbonate solution
`(pH9)
`- extract twice with a total of dichloromethane canned product (100 mL; 1.56 moles; 100.00 mL; 132.50 g; [Actual])
`- filter the organic extract over sodium sulfate, concentrate, and dry under vacuum = 2.603g Base
`
`Hydrochloride precipitation:
`- take up 2.603g base (corresponds to 11.75mmol) in 17.5ml MEK
`- add 0.235ml water while stirring
`- add 1.49ml (corresponds to 11.75mmol) trimethylchlorosilane
`- stir for another 90 minutes in the ice bath
`- filter off by suction; wash the solid again with MEK and suction dry = 2.60g Hydrochloride (cream-colored solid)
`
`Powder diffractometry:
`
`Theor. yield:
`Yield:
`Appearance:
`Fusion point:
`
`PG1026-001-1-1, Hydrochloride: Polymorph B
`
`4.08g hydrochloride
`PG1026 (2.6 g; 0.64 equiv; 10.09 mmoles; 2.60 g; 63.80% yield; [Actual])
`cream-colored solid
`199-201°C
`
`HIGHLY CONFIDENTIAL
`
`
`GRT-NUC00056650_T
`
`Page 3 of 12
`
`

`
`
`Translated from the German
`Ruth Boggs, MA, CT | ATA-Certified Translator (#62196) for German <> English | rutheboggs@gmail.com
`
`Characterization of dichloromethane, canned product
`
`Material Data
`
`
`
`Phase
`
`Strength
`
`CAS
`75-09-2
`Solvent
`Role
`Synonym Methylenchloride [1 more entry]
`Liquid (Molecular; Observed)
`100 wt/wt% (estimated) in none
`1.325 g/mL
`Density
`MF CH2CI2
`84.93 (calculated)
`MW
`-95 °C
`40 °C
`50.67 g/100-mL
`
`MP
`
`BP
`
`Solubility
`
`
`
`
`
`
`
`
`
`
`
`
`
`Chart Data
`Method
`Source
`Format
`Location
`
`Mass Spectrum
`IntelliChem ChemSeek
`JDX
`ChemSeek4
`
`Title Methylene Chloride
`Number of Points 32
`Observed Frequency 0
`Origin NIST Standard Reference Data
`
`HIGHLY CONFIDENTIAL
`
`
`GRT-NUC00056651_T
`
`Page 4 of 12
`
`

`
`
`Translated from the German
`Ruth Boggs, MA, CT | ATA-Certified Translator (#62196) for German <> English | rutheboggs@gmail.com
`
`
`
`
`
`M/Z
`
`
`
`HIGHLY CONFIDENTIAL
`
`
`GRT-NUC00056652_T
`
`Page 5 of 12
`
`

`
`
`Translated from the German
`Ruth Boggs, MA, CT | ATA-Certified Translator (#62196) for German <> English | rutheboggs@gmail.com
`
`Characterization of dichloromethane, canned product
`Material Data
`
`
`
`Phase
`
`Strength
`
`CAS
`75-09-2
`Solvent
`Role
`Synonym Methylenchloride [1 more entry]
`Liquid (Molecular; Observed)
`100 wt/wt% (estimated) in none
`1.325 g/mL
`Density
`MF CH2CI2
`84.93 (calculated)
`MW
`-95 °C
`40 °C
`50.67 g/100-ml
`
`MP
`
`BP
`
`Solubility
`
`
`
`
`
`
`
`
`
`Chart Data
`
`
`Method
`Source
`Format
`Location
`
`IR Spectrum
`IntelliChem ChemSeek
`JDX
`ChemSeek4
`
`Title Methylene Chloride
`Number of Points 880
`Observed Frequency 0
`Origin Sadtler Research Labs Under US-EPA Contract
`Owner NIST Standard Reference Data Program
`
`HIGHLY CONFIDENTIAL
`
`
`GRT-NUC00056653_T
`
`Page 6 of 12
`
`

`
`
`Translated from the German
`Ruth Boggs, MA, CT | ATA-Certified Translator (#62196) for German <> English | rutheboggs@gmail.com
`
`1/CM
`
`
`
`
`
`
`
`
`
`HIGHLY CONFIDENTIAL
`
`
`GRT-NUC00056654_T
`
`Page 7 of 12
`
`

`
`
`Translated from the German
`Ruth Boggs, MA, CT | ATA-Certified Translator (#62196) for German <> English | rutheboggs@gmail.com
`
`Characterization of methylethylketone, canned product
`
`
`Material Data
`
`
`
`
`
`
`
`
`
`CAS
`Role
`
`Synonym
`
`Phase
`
`Strength
`
`78-93-3
`Solvent
`Ethylmethylketone [4 more
`entries]
`Liquid (Molecular; Observed)
`100 wt/wt% (estimated) in none
`0.8052 g/mL
`Density
`MF C4H8O
`72.11 (calculated)
`MW
`-86 °C
`79.6 °C
`60.65 g/100-mL
`
`MP
`
`BP
`
`Solubility
`
`
`
`
`
`Chart Data
`
`Method
`Source
`Format
`Location
`
`Mass Spectrum
`IntelliChem ChemSeek
`JDX
`ChemSeek4
`
`Title 2-Butanone
`Number of Points 14
`Observed Frequency 0
`Origin NIST Standard Reference Data
`
`HIGHLY CONFIDENTIAL
`
`
`GRT-NUC00056655_T
`
`Page 8 of 12
`
`

`
`
`Translated from the German
`Ruth Boggs, MA, CT | ATA-Certified Translator (#62196) for German <> English | rutheboggs@gmail.com
`
`
`
`
`
`M/Z
`
`
`
`
`
`HIGHLY CONFIDENTIAL
`
`
`GRT-NUC00056656_T
`
`Page 9 of 12
`
`

`
`
`Translated from the German
`Ruth Boggs, MA, CT | ATA-Certified Translator (#62196) for German <> English | rutheboggs@gmail.com
`
`Characterization of methylethylketone, canned product
`
`Material Data
`
`
`
`CAS 78-93-3
`Role Solvent
`
`Synonym Ethylmethylketone [4 more entries]
`
`Phase Liquid (Molecular; Observed)
`
`Strength 100 wt/wt% (estimated) in none
`Density 0.8052 g/mL
`MF C4H8O
`MW 72.11 (calculated)
`-86 °C
`
`MP
`BP 79.6 °C
`Solubility 60.65 g/100-mL
`
`
`
`
`
`
`
`
`
`
`
`Chart Data
`
`Method
`Source
`Format
`Location
`
`IR Spectrum
`IntelliChem ChemSeek
`JDX
`ChemSeek4
`
`Title 2-Butanone
`
`Number of Points 880
`
`Observed Frequency Sadtler Research Labs Under US-EPA Contract
`
`Origin NIST Standard Reference Data Program
`
`HIGHLY CONFIDENTIAL
`
`
`GRT-NUC00056657_T
`
`Page 10 of 12
`
`

`
`
`Translated from the German
`Ruth Boggs, MA, CT | ATA-Certified Translator (#62196) for German <> English | rutheboggs@gmail.com
`
`
`
`I/CM
`
`HIGHLY CONFIDENTIAL
`
`
`GRT-NUC00056658_T
`
`Page 11 of 12
`
`

`
`RUTH BOGGS, MA, CT
`ATA-Certified Translator (#62196) & Interpreter, English <> German
`_________________________________________________________________________________
`4111 Port Rae Lane • Fairfax, Virginia 22033 • Tel. (703) 378-9305 • FAX (703) 995-0767
`
`CERTIFICATION
`
` hereby certify that
`
`
`
` I
`
`I am a German into English and English into German translator, certified by the
`(1)
`American Translators Association;
`
`I have translated and/or reviewed the translation of the following document(s)
`(2)
`from German into English:
`
`
`
`GRT-NUC00056648-58
`
`The attached English translation is a true and correct translation of the German
`(3)
`language source document to the best of my knowledge and belief.
`
`I declare that all statements made herein of my own knowledge are true, and all
`(4)
`statements made on information and belief are believed to be true. I understand that
`willful false statements and the like are punishable by fine or imprisonment, or both.
`
`
`
`
`
`
`
`
`
`
`Date: February 26, 2015
`
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`________________________
`
`Ruth Boggs, MA, CT
`
`
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`Page 12 of 12