Translated from the German
`Ruth Boggs, MA, CT | ATA-Certified Translator (#62196) & Interpreter | rutheboggs@gmail.com
`
`Laboratory Journal – Grünenthal GmbH
`
`
`
`HIGHLY CONFIDENTIAL
`
`
`
`GRT-NUC00110737_T
`
`Page 1 of 37
`
`Grunenthal GmbH Exhibit 2020
`Rosellini v. Grunenthal GmbH
`IPR2016-00471
`
`

`
`Translated from the German
`Ruth Boggs, MA, CT | ATA-Certified Translator (#62196) & Interpreter | rutheboggs@gmail.com
`
`
`
`
`
`HIGHLY CONFIDENTIAL
`
`
`
`GRT-NUC00110738_T
`
`Page 2 of 37
`
`

`
`Translated from the German
`Ruth Boggs, MA, CT | ATA-Certified Translator (#62196) & Interpreter | rutheboggs@gmail.com
`
`
`
`
`
`HIGHLY CONFIDENTIAL
`
`
`
`GRT-NUC00110739_T
`
`Page 3 of 37
`
`

`
`Translated from the German
`Ruth Boggs, MA, CT | ATA-Certified Translator (#62196) & Interpreter | rutheboggs@gmail.com
`
`
`
`
`
`
`
`
`
`5 5 1 9 1
`
`
`
`
`
`HIGHLY CONFIDENTIAL
`
`
`
`GRT-NUC00110740_T
`
`Page 4 of 37
`
`

`
`Translated from the German
`Ruth Boggs, MA, CT | ATA-Certified Translator (#62196) & Interpreter | rutheboggs@gmail.com
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Grünenthal GmbH
`
`Laboratory Journal
`
`
`
`Department:
`
`
`
`FE – PD
`
`
`
`
`
`
`
`Laboratory area:
`
`Laboratory Dr. Griebel
`
`User / project:
`
`Date issued:
`
`Date turned in:
`
`
`
`
`
`
`
`MARITA MUELLER
`
`July 31, 2002
`
`
`
`August 13, 2003
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Laboratory Journal No.:
`
`
`
`** 0609 **
`
`HIGHLY CONFIDENTIAL
`
`
`
`GRT-NUC00110741_T
`
`Page 5 of 37
`
`

`
`Translated from the German
`Ruth Boggs, MA, CT | ATA-Certified Translator (#62196) & Interpreter | rutheboggs@gmail.com
`
`CONFIDENTIAL
`
`
`
`
`
`
`
`
`
`
`
`
`
`[Grünenthal logo]
`
`User guidelines for maintaining a Lab Journal:
`
`1. The objective of this lab journal is to protect all patentable
` Grünenthal inventions from the time when they were made (first
`
`inventor principle). The idea for, the implementation of, and the
`
`continuous work on the invention must be reproducible. Therefore, the
`
`lab journal contains all of the user’s experiments and observations. All
`
`entries (descriptions of methods, reaction conditions, results) shall
`
`appear by date and in the order they were performed/made.
` To maintain continuity, it is important to document all downtimes such
`
`as sick leave, vacation, equipment failure, ordering material, work on
` multiple projects, etc. by entering them in the lab journal.
`2. Please start each entry with the date and the first three places of the
`
`project code (if possible). Please end each daily entry with date and
`
`signature. All entries are made on front and backside, without gaps,
`
`legibly, with ink pen, ballpoint pen, or magic marker (blue or black;
` waterproof pen).
`3. Please enter all descriptions, specifications, materials and results
`
`related to the experiment in the precise order of dates. The objective
` must be that any employee can continue and/or reproduce the work. If
`
`applicable, please glue any sheets of findings or results into the lab
`
`journal and sign them in such a manner that the signature spans from
`
`the glued-in sheet to the lab journal page. Voluminous records may be
`
`collected separately. The lab journal must contain an appropriate
`
`reference to these collected documents.
`4. Please make sure that errors are crossed out and dated and initialed.
` Retroactive changes must bear the current date and initials and be
`
`signed by the head of the laboratory.
`5. Each page must be initialed by the responsible head of laboratory
`
`and reviewed and countersigned by a knowledgeable witness who
`
`does not report to said head of laboratory and is not involved in the
`
`project.
`
`6. A table of contents may be prepared.
`
`7. Please turn in the lab journal for central archiving (FE-DI) after it is
`
`completed, but no later than one year after it was issued. New lab
`
`journals are issued centrally by FE-DI. Any copies for personal use
`should be prepared prior to turning in the lab journal.
`
`
`8. The lab journal must be kept in a safe place and is intended for
`
`internal use only. Please notify your head of laboratory immediately in
`
`case a lab journal gets lost. The lab journal must be kept under lock
`
`and key during non-working hours.
`
`HIGHLY CONFIDENTIAL
`
`
`
`GRT-NUC00110742_T
`
`
`
`
`
`Page 6 of 37
`
`

`
`Translated from the German
`Ruth Boggs, MA, CT | ATA-Certified Translator (#62196) & Interpreter | rutheboggs@gmail.com
`
`CONFIDENTIAL
`
`
`
`
`
`
`Table of Contents
`
`
`
`
`
`Table of Contents, Lab Journal 0609
`
`
`Page
`
`1
`2
`
`3
`
`4
`
`5
`
`
`6
`
`
`7
`
`
`8
`
`
`9
`10
`
`11
`
`12
`13
`
`14
`
`15
`
`
`16
`
`17
`
`18
`
`
`19
`
`
`
`20
`
`
`21
`
`
`
`
`
`Batch
`
`
`Batch, Work-up, DC, HCI-Precipitation, NMR
`OZ-3678-1-3
`DC, AB
`GB-19
`OZ-3656-1-24 Work-up, DC, NMR
`OZ-3657-1-26 Batch
`OZ-3678-1-3
`DC, AB
`OZ-3656-1-24 DC, AB
`OZ-3678-2-1
`Batch
`OZ-3678-2-1 Work-up, DC
`OZ-3678-1-3 Work-up
`OZ-3657-1-26 DC, Work-up
`OZ-3678-1-3
`AB
`GB-23-1-1
`Batch
`OZ-3678-2-1 Work-up, NMR
`OZ-3657-1-26 Drying, NMR
`OZ-3657
`HCI-Precipitation
`GB-23-1-1
`Boil with NaOH
`OZ-3657
`Work-up, DC, Drying, NMR, DC
`Work-up, DC, HCI-Precipitation, Citrate-
`Precipitation
`GB-23-1-1
`GB-Bu521-3-1 Batch, Work-up, DC, NMR
`GB-23-1-1
`DC, SC, NMR
`OZ-3657-1-26 DC, AB
`OZ-3503-2-3
`HCI-Precipitation, Work-up, DC
`GB-23-1-1
`NMR, LC/MS
`GB-Bu41IE
`HCI-Precipitation, Work-up, DC, NMR
`OZ-3678-2-1
`DC, AB
`GB-26-1-1
`Batch
`GB-23-1-2
`Batch
`GB-Bu41IE
`DC, AB
`GB-Bu521-3-1 DC, AB
`Venlafaxin II-4 Filter by suction, NMR, DC
`GB-26-1-1
`Batch
`GB-Bu347-1-1 Batch
`GB-23-1-1
`AB
`GB-23-1-2
`Work-up, DC, NMR
`OZ-3678-2-2
`Batch
`GB-Bu347-1-1 Work-up, HCI-Precipitation
`
`Work-up, DC, NMR
`GB-26-1-1
`GB-BU347-1-1 Precipitation
`OZ-3678-2-2
`Boil with NaOH
`OZ-3278-1-5
`Purification, NMR
`GB-26-1-1
`HCI-Precipitation, DC
`GB-26-1-1
`DC, NMR
`GB-Bu351-1-1 Batch Step 1
`OZ-3678-2-2 Work-up, DC, HCI-Precipitation, NMR
`OZ-3278-1-5
`Purification, NMR
`GB-Bu347-1-1 Drying, AB
`GB-23-1-2
`Citrate-Precipitation
`GB-Bu351-1-1 Batch Step 2
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Page
`
`
`Jul. 6, 2003 [initialed]
`
`Page
`
`31
`32
`
`33
`
`34
`
`35
`
`
`36
`
`
`37
`
`38
`39
`
`
`40
`
`41
`42
`
`43
`
`
`44
`
`45
`
`46
`
`47
`48
`49
`
`
`50
`
`51
`
`52
`
`
`53
`
`
`54
`
`
`
`Batch
`
`
`Batch
`OZ-3265-1-3
`Batch
`OZ-3245-1-3
`OZ-3265-1-3 Work-up, DC, SC, AB
`OZ-3266-1-3
`Batch, Work-up, DC, HCI-Precipitation
`OZ-3245-1-3 Work-up, DC, AB
`OZ-3251-1-2
`Batch
`OZ-3266-1-3
`Filter by suction, SC
`GB-Bu351-1-2 Work-up
`OZ-3266-1-3
`HCI-Precipitation, NMR
`OZ-3251-1-2 Work-up, DC, NMR
`OZ-3269-1-2
`Batch
`OZ-3251-1-2
`AB
`OZ-3269-1-2 Work-up
`GB-BU351-1-2 HCI-Precipitation, DC, NMR
`OZ-3266-1-3
`DC, AB
`OZ-3269-1-2
`DC, SC, AB
`OZ-3270-1-2
`Batch, Work-up, DC, NMR
`
`Batch
`GB-40-1-1
`Batch, Work-up, DC,NMR
`GB-40-1-1
`NMR, HCI-Precipitation, NMR
`OZ-3270-1-2
`NMR, SC
`GB-40-1-1
`MS, HCI-Precipitation, NMR
`GB-40-1-1
`HCI-Precipitation
`GB-Bu-41 I E
`Filter by suction, NMR, AB
`GB-Bu-41 I E
`GB-Bu347-1-3 Batch
`Bu22
`Release of base, Batch
`Bu22
`Work-up, HPLC, AB
`GB-Bu347-1-3 Work-up, HCI-Precipitation
`OZ-Bu22-1-2
`Batch
`GB-Bu347-1-3 Filter by suction AB
`GB-Bu351-1-3 Batch
`Bu22
`2nd Release
`Bu22
`Work-up, AB, 3rd Release
`Bu22
`4th Release, Work-up, HPLC
`Bu22
`Work-up, HPLC, AB
`GB-Bu351-1-3 Work-up
`HCI-Precipitation, DC, NMR, amount of
`rotation
`GB-Bu351-1-3
`Batch
`OZ-3590-1-5
`OZ-3590-1-5 Work-up, HCI-Precipitation
`GB-23-1-3
`Batch
`OZ-3590-1-5
`SC, NMR
`GB-Bu351-1-3 AB
`GB-23-1-3
`Work-up
`GB-40-1-1
`DC, AB
`GB-23-1-3
`Work-up, DC, NMR
`OZ-3590-1-5
`SC, DC
`OZ-3590-1-5
`AB
`GB-Bu322-1-2 Batch, Work-up, HCI-Precipitation
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`HIGHLY CONFIDENTIAL
`
`
`
`GRT-NUC00110743_T
`
`Page 7 of 37
`
`

`
`Translated from the German
`Ruth Boggs, MA, CT | ATA-Certified Translator (#62196) & Interpreter | rutheboggs@gmail.com
`
`Page
`
`22
`
`23
`
`24
`
`25
`
`26
`
`
`27
`
`
`28
`
`
`29
`
`
`
`30
`
`31
`
`
`Batch
`
`
`Freeze-drying, Drying, DC, AB
`GB-23-1-2
`Purification, NMR
`OZ-3278-1-5
`GB-Bu351-1-1 Work-up, HCI-Precipitation, DC, NMR,
`
`Amount of rotation, AB
`GB-Bu322-1-1 Batch, Work-up, HCI-Precipitation, NMR,
`
`Crystal structure analysis, AB
`OZ-3657
`HCI-Precipitation, Batch
`GB-32-1-1
`Batch
`GB-32-1-1
`Work-up, NMR
`OZ-3657
`Work-up, NMR
`OZ-3243-1-3
`Batch
`GB-32-1-1
`Work-up, NMR
`OZ-3243-1-3 Work-up, DC, AB
`OZ-3249-1-3
`Batch
`OZ-3249-1-3 Work-up, DC, NMR
`GB-Bu351-1-2 Drying
`GB-Bu41 I E
`HCI-Precipitation, Batch
`GB-Bu41 I E
`Work-up, NMR
`GB-Bu351-1-2 Step 1: Prod. Zn(BH)4- solution
`OZ-3249-1-3
`AB
`GB-Bu347-1-2 Batch
`GB-Bu347-1-2 Batch, Work-up, HCI-Precipitation, AB
`GB-Bu351-1-2 Batch
`GB-Bu351-1-2 Batch, Step 2
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Page
`
`55
`
`56
`
`57
`
`
`58
`
`59
`
`60
`
`
`61
`
`62
`
`
`63
`
`64
`
`65
`
`
`Batch
`
`
`Turn in, AB
`GB-23-1-3
`Batch, Work-up, DC
`GB-40-2-1
`Batch, Work-up, HCI-Precipitation
`GB-47-1-1
`Batch
`OZ-3592-2-8
`GB-Bu322-1-2 Filter by suction, NMR
`GB-47-1-1
`Filter by suction, DC, NMR
`OZ-3592-2-8 Work-up, DC, NMR
`GB-40-2-1
`SC, NMR
`GB-Bu322-1-2 AB
`OZ-3592-2-8
`DC, AB
`GB-Bu322-1-3 Batch
`GB-Bu322-1-3 Work-up, HCI-Precipitation, NMR
`GB-40-2-1
`HPLC
`OZ-3610-1-8
`Batch
`OZ-3610-1-8
`Batch, Work-up, DC, HCI-Precipitation
`GB-47-1-1
`Hydration, Work-up
`OZ-BN 35-2-2 Batch, Work-up
`GB-47-1-1
`Filter by suction, NMR, LC/MS
`OZ-3610-1-8
`Filter by suction, NMR
`OZ-BN35-2-2 Work-up
`GB-47-1-1
`AB
`OZ-BN35-2-2
`Filter by suction
`OZ-3610-1-8
`Crystallization experiments, SC
`OZ-3610-1-8
`SC, NMR
`
`HIGHLY CONFIDENTIAL
`
`
`
`GRT-NUC00110743_T
`
`Page 8 of 37
`
`

`
`Translated from the German
`Ruth Boggs, MA, CT | ATA-Certified Translator (#62196) & Interpreter | rutheboggs@gmail.com
`
`CONFIDENTIAL
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Table of Contents
`
`
`
`
`
`Page
`
`65
`66
`
`67
`
`68
`
`
`69
`
`70
`
`71
`
`72
`
`73
`
`74
`
`75
`
`76
`
`77
`
`
`78
`
`
`79
`
`80
`
`81
`
`
`82
`
`83
`
`
`84
`
`
`85
`
`86
`
`87
`
`
`Batch
`
`
`GB-EM907-2-1 Batch
`GB-EM907-2-1 DC, Work-up
`OZ-3610-1-8
`2. SC
`OZ-3610-1-8
`2. SC, NMR
`GB-59-1-1
`HCI-Precipitation
`GB-59-1-1
`Work-up, NMR
`OZ-3610-1-8
`3. SC, AB
`GB-59-1-2
`HCI-Precipitation
`GB-59-1-2
`HCI-Precipitation, Work-up, NMR, AB
`GB-59-1-1
`AB
`OZ-3571-2-6
`Batch, Work-up, DC, NMR
`GB-EM907-2-1 SC, NMR
`OZ-3571-2-6
`HCI-Precipitation, NMR
`GB-WH153-1-0 Batch, Work-up, NMR, HPLC, GC
`GB-WH153-1-1 Batch
`GB-WH153-1-0 SC, NMR
`GB-WH153-1-1 Work-up
`GB-WH153-1-2 Batch
`GB-WH153-1-2 Work-up
`GB-WH153-1-1 HCI-Precipitation
`GB-WH153-1-1 NMR, GC
`GB-WH 153-1-2 HCI-Precipitation
`GB-65-2-1
`Batch, Work-up
`GB-65-1-1
`Batch, Work-up
`GB-65-1-1
`DC, NMR, GC
`GB-65-2-1
`DC, NMR, GC
`GB-WH153-1-2 NMR, GC,
`GB-WH 153-1-1 NMR, DC
`OZ-3571-2-6
`HCI-Precipitation
`GB-65-2-1
`Filter by suction and Work-up
`GB-WH 153-1-2 NMR, GC
`GB-WH153-1-1 NMR
`GB-65-1-2
`Batch
`GB-65-1-3
`Batch
`OZ-3571-2-6
`Filter by suction and Work-up
`GB-65-1-2
`Work-up, NMR, GC
`GB-65-1-3
`Work-up, NMR, GC
`GB-WH 153-1-1 Recrystallization
`GB-WH 153-1-2 Reprecipitation, Recrystallization, NMR
`GB-WH153-1-2 Recrystallization
`GB-WH153-1-1 Recrystallization
`GB-Bu164-1-1 Batch
`GB-65-1-2
`Elementary analysis
`GB-Bu351-2-1 Batch
`GB-Bu164-1-1 Work-up, DC
`GB-Bu351-2-1 Work-up, DC
`GB-Bu322-2-1 Batch
`GB-Bu351-2-1 SC, NMR
`GB-Bu322-2-1 Work-up, HCI-Precipitation
`GB-Bu322-2-1 SC, NMR
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Page
`
`
`2/21/2003 [initialed]
`
`Page
`
`94
`95
`
`
`
`
`96
`
`97
`
`98
`
`99
`
`
`100
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Batch
`
`
`AB
`GB-65-1-4
`AB
`GB-65-1-5
`DC, NMR, AB
`GB-71-1-3
`DC, NMR, AB
`GB-71-1-4
`DC, NMR, AB
`GB-71-1-5
`GB-Bu351-3-1 Work-up, DC
`GB-Bu351-4-1 Batch, AB
`GB-71-1-6
`Batch
`GB-71-1-6
`Batch, Work-up, DC, NMR
`GB-Bu322-2-2 Batch
`GB-71-1-6
`NMR, GC
`GB-Bu351-5-1 Batch
`GB-JH1003-1-1 Batch
`GB-Bu322-2-2 Work-up
`GB-Bu351-5-1 Work-up
`GB-65-1-6
`Batch
`GB-Bu322-2-2 DC
`GB-Bu351-5-1 DC
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`HIGHLY CONFIDENTIAL
`
`
`
`GRT-NUC00110744_T
`
`Page 9 of 37
`
`

`
`Translated from the German
`Ruth Boggs, MA, CT | ATA-Certified Translator (#62196) & Interpreter | rutheboggs@gmail.com
`
`
`Batch
`GB-Bu164-1-1 SC, NMR
`GB-Bu164-1-1 SC
`GB-65-1-4
`Batch
`GB-65-1-5
`Batch
`GB-65-1-5
`Batch, Work-up, DC
`GB-65-1-4
`Work-up, DC, NMR, GC
`GB-65-1-5
`DC, NMR, GC
`GB-Bu164-1-1 DC, NMR, GC
`GB-71-1-1
`Batch
`GB-71-1-1
`Batch
`GB-71-1-2
`Batch
`GB-Bu164-1-1 HCI-Precipitation, NMR
`GB-71-1-1
`Work-up, DC, NMR, AB
`GB-71-1-2
`Work-up, DC, NMR, AB
`GB-71-1-3
`Batch
`GB-71-1-4
`Batch
`GB-71-1-5
`Batch
`GB-Bu164-1-1 AB
`GB-Bu351-3-1 Batch
`GB-71-1-3
`Work-up
`GB-71-1-4
`Work-up
`GB-71-1-5
`Work-up
`
`Page
`
`88
`
`
`89
`
`90
`
`
`91
`
`
`92
`
`
`93
`
`
`94
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Page
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Batch
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`HIGHLY CONFIDENTIAL
`
`
`
`GRT-NUC00110744_T
`
`Page 10 of 37
`
`

`
`Translated from the German
`Ruth Boggs, MA, CT | ATA-Certified Translator (#62196) & Interpreter | rutheboggs@gmail.com
`
`
`
`
`
`
`
`CONFIDENTIAL
`Lab Journal No.: ** 0609 **
`
`Project:
`
`FHW
`[Translator’s note: Please note initials and dates in source document margins]
` GB-Bu41 I E (BN68)
`
`
`
`
`Hydrochloride Precipitation
`
`[Grünenthal logo]
`12
`
`
`
`Project Code: FHWF99 Release code:
`Hydrochloride precipitation M [g/mol]
`Base HPLC-Fr. II
`251.36
`Methyl ethyl ketone
`
`Water
`
`Trimethylchlorosilane
`
`
`
`Apparatus:
`100 ml-round flask, magnetic stirrer, dropping funnel, thermometer.
`Patent specification EP 0 693 475 B1:
`
`Technician: M. Mueller Date: Aug. 15, 2002
`m [g]
`n [mmol]
`V [ml]
`7.60
`30.34
`
`
`
`
`
`
`30.24
`
`45.14
`0.60
`3.82
`
`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:
`
`Workup:
`
`DC:
`
`1H-NMR:
`
`Date:
`Date:
`
`
`
`
`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
`GB-Bu41 I E x HCl: OK.
`
`
`Nov. 19, 2002
`Feb. 28, 2003
`
`
`
`
`
`
`
`read and understood:
`
`Signature:
`Signature:
`
`
`
`
`[initialed]
`[initialed]
`
`
`
`Flow agent: ethyl acetate / methanol = 3/1
`
`HIGHLY CONFIDENTIAL
`
`
`
`GRT-NUC00110756_T
`
`Page 11 of 37
`
`

`
`Translated from the German
`Ruth Boggs, MA, CT | ATA-Certified Translator (#62196) & Interpreter | rutheboggs@gmail.com
`
`
`CONFIDENTIAL
`Project:
`FKU, FHW
`
`
`
`
`
`
`
`
`
`
`[Grünenthal logo]
`14
`Lab Journal No.: ** 0609 **
`
`
`[Translator’s note: Please note initials and dates in source document margins]
`
`GB-23-1-2
`
`
`
`Release code:
`
`
`
`Technician: M. Mueller
`
`
`
`
`Date: August 16, 2002
`
`Batch size:
`CH125
`Toluene
`Phenyl chloroformate
`5N NaOH
`Ethylene glycol
`
`
`Apparatus:
`Execution:
`
`
`
`
`
`M [g/mol] Density Factor n [mmol] m [g] V [ml]
`277.83
`
`1.0
`4.9
`1.38
`
`
`
`
`
`85.01
`156.57
`1.246
`5.4
`0.85
`0.68
`
`
`
`
`9.90
`
`
`
`
`41.60
`
`
`
`
`
`
`1.1
`
`100 ml-round flask, magnetic stirrer, oil bath, thermometer, reflux cooler, syringe.
`Release base from CH125 citrate with potassium carbonate / dichloromethane.
`Heat base in toluene to reflux. Add phenyl chloroformate dropwise.
`Reflux for 4 hours and then let cool down.
`
`[Aug. 16, 2002 – initialed]
`Theor. Yield:
`
`Yield (raw):
`
`Appearance:
`
`Fusion point:
`
`
`
`Date:
`Date:
`
`8.70 g hydrochloride
`m = 8.537 g (corresponds to 98.1% of theoretical)
`white solid
`150 – 152 oC
`
`
`
`Nov. 19, 2002
`Feb. 28, 2003
`
`Signature:
`
`
`
` read and understood Signature:
`
`[initialed]
`[initialed]
`
`
`
`
`HIGHLY CONFIDENTIAL
`
`
`
`GRT-NUC00110758_T
`
`Page 12 of 37
`
`

`
`Translated from the German
`Ruth Boggs, MA, CT | ATA-Certified Translator (#62196) & Interpreter | rutheboggs@gmail.com
`
`
`
`
`
`
`
`CONFIDENTIAL
`Lab Journal No.: ** 0609 **
`
`Project:
`FHW, FKU
`[Translator’s note: Please note initials and dates source document margins]
`GB-Bu347-1-1
`
`[Grünenthal logo]
`16
`
`
`
`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)-dimethyl amine, hydrochloride (+22)
`
`10g (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 three hours while stirring vigorously, whereby the hydrochloride crystallized out.
`9.8 g (91% of theoretical) (22) were obtained.
`Melting point: 120 oC (breakdown)
`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.
`
`
`Theoretical yield:
`
`
`
`Yield:
`
`
`
`
`
`
`
`1.28 g base
`1.47 g hydrochloride
`n/a
`
`Date:
`Date:
`
`
`
`
`Nov. 19, 2002
`Feb. 28, 2003
`
`
`
`
`Signature:
`
`
`
` read and understood Signature:
`
`[initialed]
`[initialed]
`
`
`
`
`
`
`HIGHLY CONFIDENTIAL
`
`
`
`GRT-NUC00110760_T
`
`Page 13 of 37
`
`

`
`Translated from the German
`Ruth Boggs, MA, CT | ATA-Certified Translator (#62196) & Interpreter | rutheboggs@gmail.com
`
`
`
`
`
`
`
`CONFIDENTIAL
`Lab Journal No.: ** 0609 **
`
`Project:
`
`FHW
`[Translator’s note: Please note initials and dates source document margins]
`
`[Grünenthal logo]
`18
`
`
`
`
`Workup:
`
`Hydro-
`chloride
`precipi-
`tation:
`
`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.
`To make seed crystals, a spatula tip of solution is mixed with diethyl ether and n-hexane in a test tube,
`scratched with a glass rod, and kept closed overnight in the refrigerator.
`
`
`[Stirring vigorously, add 254 ml diisopropyl ether dropwise over 2 hours and continue to stir overnight at room
`temperature.]
`
`
`
`
`
`
`
`
`
`
`
`
`
`Workup:
`
`
`
`
`
`
`
`
`
`DC:
`
`
`
`Wash with 50 ml each 2.5N NaOH, water, 1N HCl and saturated NaCl solution. Filter the
`organic phase over sodium sulfate and concentrate.
`Heat the residue with ethylene glycol and 5N NaOH over 4.5 hours to 110 oC. A white solid
`deposited at the rim of the glass in the yellow solution. Cool down to room
`
`
`temperature.
`
`Dilute with 80 ml water and extract three times with 50 ml each dichloromethane
`(ethylene glycol remains in the aqueous phase). Filter the extract over sodium sulfate,
`concentrate and dry under vacuum. = 1.256 g yellow oil with solid particles (contains
`maximally 1.066 g base).
`Mix the oil with 3ml n-hexane and stir vigorously overnight.
`
`GB-26-1-1-1
`
`Flow agent: ethyl acetate/methanol = 3/1
`
`
`
`
`
`
`
`1H-NMR:
`
`
`
`Solvent: CDCl3
`GB-26-1-1-4 raw base:
`
`Product + impurity
`
`
`
`Date:
`Date:
`
`
`
`
`Nov. 19, 2002
`Feb. 28, 2003
`
`
`
`
`Signature:
`
`
`
` read and understood Signature:
`
`
`[initialed]
`[initialed]
`
`
`
`
`HIGHLY CONFIDENTIAL
`
`
`
`
`GRT-NUC00110762_T
`
`Page 14 of 37
`
`

`
`Translated from the German
`Ruth Boggs, MA, CT | ATA-Certified Translator (#62196) & Interpreter | rutheboggs@gmail.com
`
`
`
`
`
`
`
`CONFIDENTIAL
`Lab Journal No.: ** 0609 **
`Project:
`FHW, FKS, FHV
`[Translator’s note: Please note initials and dates of source document margins]
`
`[Grünenthal logo]
`
`19
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`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.
`
`
`
`Wash with 50 ml each 2.5N NaOH, water, 1N HCl and saturated NaCl solution.
`Filter the organic phase over sodium sulfate and concentrate. A clear yellow oil remains
`as residue.
`Stir the residue with ethylene glycol and 5N NaOH for 7 hours at 126 oC bath
`temperature. The solution is clear and yellow-brown. Stir overnight at room temperature.
`
`
`
`Briefly boil 17.73 g base in 300 ml acetone while stirring. Filter by suction and suction
`solid dry. = (9.3484 + 5.457 =) 14.941 g solid. Fusion point = 308-310 oC.
`Concentrate the mother liquor and dry the residue under vacuum.
`
`
`
`
`
`
`
`
`
`
`
`
`1H-NMR:
`
`
`
`Solvent: DMSO
`OZ-3278-1-5 solid: impure
`
`
`
`
`
`
`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.
`
`Hydrochloride- Dissolve 0.247 g (corresponds to 1.2 mmol) base in 1.81 ml methyl ethyl ketone and first add 2
`Precipitation:
`drops of water while stirring and cooling with ice. Dissolve 0.15 ml TMCS in 1.8 ml
`
`methyl ethyl ketone and slowly add dropwise at 5 oC. After 10 minutes, add 10 ml diethyl ether and
`
`
`
`
`continue stirring. After 10 minutes, a white solid precipitated.
`
`
`Filter by suction; wash the solid thoroughly with diethyl ether and suction dry.
`
`
`= 0.141g white solid (corresponds to 48.62% AB relative to the raw base).
`
`
`The mother liquor does not contain any product and is discarded.
`
`DC:
`
`Date:
`Date:
`
`
`
`
`
`
`GB-26-1-1-5
`
`Flow agent: ethyl acetate/methanol = 1 / 2
`
`Nov. 19, 2002
`Feb. 28, 2003
`
`
`
`
`
`
`
` read and understood
`
`Signature:
`Signature:
`
`[initialed]
`[initialed]
`
`
`
`
`HIGHLY CONFIDENTIAL
`
`
`
`
`GRT-NUC00110763_T
`
`Page 15 of 37
`
`

`
`Translated from the German
`Ruth Boggs, MA, CT | ATA-Certified Translator (#62196) & Interpreter | rutheboggs@gmail.com
`
`
`
`
`
`
`
`CONFIDENTIAL
`Lab Journal No.: ** 0609 **
`
`Project:
`FHW, FKS
`[Translator’s note: Please see dates and initials in source document margins]
`
`
`[Grünenthal logo]
`
`20
`
`
`
`
`
`1H-NMR:
`
`
`13C-NMR:
`
`Solvent: CDCl3 DMSO
`)
`GB-26-1-1-6 hydrochloride: ) 1 methyl group split off.
`GB-26-1-17 hydrochloride:
`)
`
`
`
`AB: ./.
`
`
`
`GB-Bu351-1-1
`
`
`
`
`
`Zinc chloride is dried in the drying pistol overnight.
`
`
`
`
`
`OZ-3678-2-2
`Add 10 ml 6N NaOH and stir for another 7 hours at 126 oC bath temperature. Allow coming to room temperature
`overnight.
`August 23, 2002
`
`
`
`GB-Bu 351-1-1
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Workup:
`
`
`
`
`
`
`
`DC:
`
`
`
`46 g dried zinc chloride are dissolved in 580 ml dried diethyl ether and filtered over
`sodium sulfate.
`Step 1: Suspend 31g sodium borohyride 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.
`
`
`Dilute with 100 ml water and extract three times with 50 ml each dichloromethane
`(ethylene glycol remains in the aqueous phase). Filter the extract over
`
`sodium sulfate, concentrate and dry under vacuum. = 1.429 g brown oil.
`
`According to DC, very little bottom traces so far.
`
`OZ-3678-2-2-1
`
`Flow agent: ethyl acetate / methanol = 3/1
`
`Hydrochloride- Dissolve 1.429 g (corresponds to 5.41 mmol) base in 8.1 ml methyl ethyl ketone
`Precipitation:
`and first add 0.11 ml water while stirring and then 0.67 ml TMCS dropwise.
`
`
`
`After 10 minutes, add 30 ml diethyl ether and continue stirring for another 30
`
`
`
`minutes.
`
`
`No solid is obtained. Remove the solvent and stir the residue for 30
`
`
`minutes in diethyl ether.
`
`
`Filter by suction; wash the solid thoroughly with diethyl ether and
`
`
`suction dry. = 0.028 g brown solid.
`
`
`The mother liquor contains only top traces and is discarded.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Date:
`Date:
`
`1H-NMR:
` Solvent: DMSO
`: OZ-3678-2-2-4 hydrochloride = reagent
`
`
`
`Nov. 19, 2002
`
`
`
`
`
`Feb. 28, 2003
`
` read and understood
`
`AB ./.
`
`Signature:
`Signature:
`
`9
`
`[initialed]
`[initialed]
`
`
`
`
`HIGHLY CONFIDENTIAL
`
`
`
`
`GRT-NUC00110764_T
`
`Page 16 of 37
`
`

`
`Translated from the German
`Ruth Boggs, MA, CT | ATA-Certified Translator (#62196) & Interpreter | rutheboggs@gmail.com
`
`
`
`
`
`
`
`CONFIDENTIAL
`Lab Journal No.: ** 0609 **
`
`Project:
`
`FHV
`[Translator’s note: Please see dates and initials in source document margins]
`
`
`[Grünenthal logo]
`
`21
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`The solid is boiled one more time in 150 ml acetone and treated again as described
`earlier. = 13.8 g yellow solid I. Fusion point: =
`Concentrate the mother liquor and dry the residue under vacuum.
`
`1H-NMR:
`
`
`
`Solvent: DMSO
`OZ-3278-I-5 solid I: impure
`
`
`
`
`
`
`
`Completely remove the solvent and dry the residue under vacuum. = 8.547 g.
`Immediately continue reaction into Bu351-1-1.
`
`Theor. Yield:
`Yield (raw):
`Appearance:
`
`9.076 g hydrochloride
`m = 8.547 g (corresponds to 94.17 % of theoretical)
`gray-green solid
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Washing with acetone repeated = 12.288 g solid II
`unsauber = impure
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Date:
`Date:
`
`
`
`Citrate-
`Precipitation
`
`
`
`
`
`
`
`with 1 eq citric acid (M = 192.13 g/mol) in methanol
`Dissolve 0.116 g base (corresponds to 0.44 mmol) in 0.23 ml methanol at 50 oC.
`Dissolve 0.085 g (corresponds to 0.44 mmol) non-aqueous citric acid at 50 oC in 0.23 ml
`methanol and drop into the base while stirring. Stir for 1 hour in the ice bath and continue
`to stir overnight 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 3 days.
`
`
`
`
`
`
`Nov. 19, 2002
`Feb. 28, 2003
`
`
`
`
`
`
`
` read and understood
`
`Signature:
`Signature:
`
`[initialed]
`[initialed]
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`HIGHLY CONFIDENTIAL
`
`
`
`
`GRT-NUC00110765_T
`
`Page 17 of 37
`
`

`
`Translated from the German
`Ruth Boggs, MA, CT | ATA-Certified Translator (#62196) & Interpreter | rutheboggs@gmail.com
`
`
`
`
`
`
`CONFIDENTIAL
`Lab Journal No.: ** 0609 **
`
`Project:
`FHW
`[Translator’s note: Please see dates and initials in source document margins]
`
`
`
`
`
`[Grünenthal logo]
`
`23
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`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.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Releasing the base: 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.
`
`Hydrochloride- Dissolve 3.94 g (corresponds to 16.75 mmol) base in 25 ml methyl ethyl ketone. While
`Precipitation:
`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.
`
`
`
`Concentrate the mother liquor and dry the residue under vacuum. = 0.311g white
`
`
`hydrochloride.
`
`DC:
`
`
`
`GB-Bu351-1-1-1 Flow agent: ethyl acetate/methanol = 1 / 1
`
`1H-NMR:
`
`
`Amount of
`rotation:
`
`Solvent: DMSO
`GB-Bu351-1-1-3 hydrochloride: Okay.
`GB-Bu351-1-1-4 hydrochloride: -23.4o (c = 0.955% in methanol)
`
`Theor. Yield:
`Yield (raw):
`Appearance:
`Fusion point:
`Date:
`
`Date:
`
`
`7.59 g hydrochloride
`
`m = 4.545 g (corresponds to 59.88% of theoretical)
`
`white solid
`
`152 – 154 oC
`
`Nov. 19, 2002
`
`Feb. 28, 2003
`
`
`
`
`
` read and understood
`
`Signature:
`Signature:
`
`
`
`[initialed]
`[initialed]
`
`
`
`
`HIGHLY CONFIDENTIAL
`
`
`
`
`GRT-NUC00110767_T
`
`Page 18 of 37
`
`

`
`Translated from the German
`Ruth Boggs, MA, CT | ATA-Certified Translator (#62196) & Interpreter | rutheboggs@gmail.com
`
`CONFIDENTIAL
`Project:
`FHW
`
`
`
`
`
`
`
`
`Lab Journal No.: ** 0609 **
`
`
`
`
`
`GB-Bu322-1-1 (BN200)
`
`[Grünenthal logo]
`
`24
`
`
`
`
`
`Date: Sept. 5, 2002
`Technician: M. Mueller
`
`Release code:
`Project Code: FHWF99
`M [g/mol] Density Factor n [mmol] m [g] V [ml]
`Batch size:
`271.83
`
`1.0
`16.7
`4.55
`
`GB-Bu351-1-1 x HCl
`
`
`
` 111.47
`Aqueous HBr
`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.
`
`Solvent: DMSO
`GB-Bu322-1-1-1 hydrochloride: OK.
`
`! Dr. Fischer (Analytics, Dr. Falk): Polymorph B? OK.
`
`4.315 g hydrochloride
`
`m = 1.647 g (corresponds to 38.17 % of theoretical)
`
`Mustard-colored solid
`
`197 – 199 oC
`
`
`Nov. 19, 2002
`Feb. 28, 2003
`
`
`
`
` read and understood
`
`
`
`Sept. 5, 2002 [initial