WO2006107964A2 - Processes to prepare 6-phenethyl-octahydro-pyrrolo [2 , 3-c] pyridine and related compounds - Google Patents

Processes to prepare 6-phenethyl-octahydro-pyrrolo [2 , 3-c] pyridine and related compounds Download PDF

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WO2006107964A2
WO2006107964A2 PCT/US2006/012498 US2006012498W WO2006107964A2 WO 2006107964 A2 WO2006107964 A2 WO 2006107964A2 US 2006012498 W US2006012498 W US 2006012498W WO 2006107964 A2 WO2006107964 A2 WO 2006107964A2
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acid
formula
racemic
dibenzoyl
compound
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PCT/US2006/012498
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French (fr)
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WO2006107964A3 (en
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Guang-Pei Chen
Xinglong Jiang
Prasad Koteswara Kapa
Joseph Mckenna
Wen-Chung Shieh
Song Xue
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Novartis Ag
Novartis Pharma Gmbh
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present invention provides efficient and cost effective ways to prepare 6-phenethyl- octahydro-pyrrolo[2,3-c]pyridine and related compounds of the following formula (I):
  • variable UR 5 are of formula (I) which attach to the backbone of formula (II) via the nitrogen in the pyrrolo ring.
  • PG benzyl or benzylic protecting group
  • n 0,1 or 2
  • Step A This step involves the formation of an aziridine ring via standard base mediated conditions.
  • Step B This step involves the formation of a secondary amine via the reaction of an alkyl bromide with excess amine in the presence of a base.
  • Step C This step involves the coupling of a secondary amine with an activated derivative of the aziridine methyl ester to form an amide substituted aziridine.
  • Step D This step involves the intramolecular cycloaddition of the aziridine to the tethered alkene through a thermally accessible azomethine ylide intermediate.
  • Step E This step involves the reduction of the amide to an amine via standard reduction conditions employing DIBAL-H.
  • Step F This step involves the removal of the benzylic protecting group using standard palladium conditions under a hydrogen atmosphere.
  • This invention provides more practical and economical processes for the manufacture of 6- phenethyl-octahydro-pyrrolo[2,3-c]pyridine and related compounds of formula (I):
  • UR 5 are compounds of formula (I) which attach to the backbone of formula (II) via the nitrogen in the pyrrolo ring.
  • Compounds of formula (II) can be used for treatment of proliferative diseases.
  • This invention discloses efficient processes for the synthesis of 6-phenethyl- octahydro-pyrrolo[2,3-c]pyridine and related compounds of formula (I).
  • R 1 is H; C 1 -C 4 alkyl; C 1 -C 4 alkenyl; C 1 -C 4 alkynyl or cycloalkyl which are unsubstituted or substituted;
  • R 2 is H; C r C 4 alkyl; C 1 -C 4 alkenyl; C 1 -C 4 alkynyl or cycloalkyl which are unsubstituted or substituted;
  • R 3 is H; -CF 3 ; -C 2 F 5 ; C 1 -C 4 alkyl; C 1 -C 4 alkenyl; C 1 -C 4 alkynyl; -CH 2 -Z or R 2 and R 3 together with the nitrogen form a het ring;
  • Z is H; -OH; F; Cl; -CH 3 ; -CF 3 ; -CH 2 CI; -CH 2 F Or -CH 2 OH;
  • R 4 is C 1 -C 16 straight or branched alkyl; C 1 -C 16 alkenyl; C 1 -C 16 alkynyl; or -C 3 -C 10 cycloalkyl; - (CH 2 ) ⁇ 6 -Z 1 ; -(CH 2 )o -6 -aryl; and -(CH 2 ) 0 . 6 -het, wherein alkyl, cycloalkyl and phenyl are unsubstituted or substituted;
  • Z 1 is -N(R 8 )-C(O)-CrC 10 alkyl; -N(R 8 )-C(O)-(CH 2 ) 1-6 -C 3 -C 7 cycloalkyl; -N(R 8 )-C(O)-(CH 2 ) 0 . 6 - phenyl; -N(R 8 )-C(O)-(CH 2 ) 1 .
  • het is a 5-7 membered heterocyclic ring containing 1- 4 heteroatoms selected from N, O and S, or an 8-12 membered fused ring system including at least one 5-7 membered heterocyclic ring containing 1, 2 or 3 heteroatoms selected from N, O, and S, which heterocyclic ring or fused ring system is unsubstituted or substituted on a carbon or nitrogen atom;
  • R 8 is H, -CH 3 , -CF 3 , -CH 2 OH or -CH 2 CI;
  • R 9 and Ri 0 are each independently H; C r C 4 alkyl; C 3 -C 7 cycloalkyl; -(CH 2 )i. 6 -C 3 -C 7 cycloalkyl; - (CH 2 ) 0-6 -phenyl; wherein alkyl, cycloalkyl and phenyl are unsubstituted or substituted, or R 9 and R 1O together with the nitrogen form het;
  • R 5 is (CH 2 ) 2 -phenyl or R 5 is a residue of an amino acid
  • n 0-5;
  • Ra and Rb are independently C 0-2 alkyl wherein one or more of the carbon atoms in the alkyl chain may be replaced by a heteroatom selected from N, and where the alkyl may be unsubstituted or substituted;
  • Rd is -Re - Q - (Rf) p (Rg) q ;
  • Rc is H or Rc and Rd together form cycloalkyl or het; where if Rd and Reform a cycloalkyl or het, R 5 is attached to the formed ring at a N atom;
  • p and q are independently 0 or 1 ;
  • Re is C 1-2 alkyl, or alkylidene, and Re may be unsubstituted or substituted;
  • Rf and Rg are each independently H; -CrC 2 alkyl; -(CH 2 )i -6 -het; -; or R 9 and R f form a ring selected from het ;
  • Het refers heterocyclic rings and fused rings containing non-aromatic heterocyclic rings.
  • Het is a 5-7 membered heterocyclic ring containing a heteroatom N 1 or an 8-12 membered fused ring system including at least one 5-7 membered heterocyclic ring containing a heteroatom N.
  • alkyl includes straight or branched chain alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl and branched pentyl, n-hexyl and branched hexyl, and the like.
  • a "cycloalkyl” group means C 3 to C 10 cycloalkyl having 3 to 8 ring carbon atoms and may be, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl.
  • cycloalkyl is cycloheptyl.
  • the chiral auxiliary (S)-naphthylethylamine is replaced by (f?)-naphthylethylamine and this results in easy chromatographic separation of the desired diastereoisomer as it eluted earlier than the undesired one.
  • the expensive chiral auxiliary is replaced with the inexpensive benzylamine and the tedious chromatography step is replaced by a simplified resolution method.
  • dibenzoyl-D-tartaric acid as the resolving agent.
  • other chiral acids may be used as resolving agents, incuding those selected from 0,0'- diacetyltartaric acid, O,0'-diacroyltartaric acid, O.O'-dibenzoyltartaric acid, O 1 O'- dicyclohexylacetyltartaric acid, O.O'-dihexahydrobenzoyltartaric acid, O 1 O'- dimethylacroyltartaric acid, methyl hydrogen diacetyltartaric acid, or any other derivatives of tartaric acid.
  • Step 1 A1 + A2 ⁇ A3
  • phenethylamine A2 (2 kg, 16.7 mol), potassium carbonate (766 g, 5.6 mol, 325 mesh), and acetonitrile (8 L) under nitrogen atmosphere.
  • 4-Bromo-1-butene A1 (576 g, 5 mol) is added slowly at 20-25 0 C over a period of 30 min.
  • the mixture is heated to 50 0 C and stirred for an additional 3 h.
  • the mixture is cooled to rt and stirred for an additional 12 h.
  • the stirrer is stopped and any solid is allowed to settle.
  • the supernatant (organic solution) is separated from the solid by siphoning.
  • Step 2 M3c + M3b ⁇ M3a
  • DW-therm 900 g, a mixture of triethoxyalkylsilane, purchased from Huber
  • the solvent is heated to 240 0 C.
  • a solution of amide A4 (443 g, 1.1 mol) in DW-therm (400 g) is added over a period of 45 min, maintaining the batch temperature at 240 0 C.
  • the mixture is stirred for an additional 20 min.
  • the mixture is cooled to rt and allowed to settle into a two-phase solution.
  • the thick bottom layer is separated and purified by chromatography (silica gel; EtOAc/heptane/ diethylamine 40:60:1) to isolate the first crop of product A5 as an solid.
  • the upper layer is concentrated under vacuum at 60 - 70 °C/0.5 mmHg until small amount of DW-therm is present.
  • the residual oil is purified by chromatography (silica gel; EtOAc/heptane/diethylamine 40:60:1) to isolate the second crop of product A5.
  • Both crops of A5 are combined and recrystallized from a mixture of terf-butyl methyl ether and heptane to afford A5 as a solid: m.p. 103 - 106 0 C.
  • (+)-dibenzoyl-D- (+)-dibenzoyl-D- tartaric acid tartaric acid
  • a 1-L flask is charged with 2-phenylethylamine A2 (47.62 g, 393 mmol), K 2 CO 3 (163.7 g, 1.184 mol), 4-bromo-1-butene A1 (35.5 g, 263 mmol), NaI ( 177 g, 1.184 mol) and DMF (500 ml_).
  • the reaction mixture is heated to 100 0 C and hold at this temperature for 22 h. Cool the reaction mixture to 20 0 C , add water (700 ml_) and TBME (700 mL).
  • the organic layer is washed with water, dried over MgSO 4 and concentrated to give yellow oil which is further purified by distillation under reduced pressure to give 35.1 g of A3 in 76% yield.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The present invention provides efficient and cost effective ways to prepare 6-phenethyl-octahydro-pyrrolo[2,3-c]pyridine and related compounds of the following formula (I).

Description

PROCESS TO PREPARE ORGANIC COMPOUNDS
Background of the Invention
The present invention provides efficient and cost effective ways to prepare 6-phenethyl- octahydro-pyrrolo[2,3-c]pyridine and related compounds of the following formula (I):
Figure imgf000002_0001
n = = 0, 1 , 2...
(0
The compounds of formula I are key intermediates for the preparation of dipeptide amides of formula (II):
Figure imgf000002_0002
wherein variable UR5 are of formula (I) which attach to the backbone of formula (II) via the nitrogen in the pyrrolo ring.
Compounds of formula (II) have been disclosed in Provisional Application No. U.S. 60/560,186, filed April 7, 2004, the disclosure of which is incorporated herein by reference. The compounds of formula (II) inhibit the binding of the Smac protein to Inhibitor of Apoptosis Proteins (IAPs). As such, compounds of formula (II) can be used for the treatment of certain proliferative diseases, including cancer.
Previous synthesis of compounds (I) involves the following reaction: Scheme 1
Figure imgf000003_0001
PG = benzyl or benzylic protecting group
Step B
Figure imgf000003_0002
n = 0,1 or 2
Step C
1) KOTMS
2) PivCI
3) amine
Figure imgf000003_0003
Figure imgf000003_0004
Figure imgf000003_0005
separate diastereomers
Figure imgf000003_0006
wherein X=H.
Step A: This step involves the formation of an aziridine ring via standard base mediated conditions.
Step B: This step involves the formation of a secondary amine via the reaction of an alkyl bromide with excess amine in the presence of a base.
Step C: This step involves the coupling of a secondary amine with an activated derivative of the aziridine methyl ester to form an amide substituted aziridine.
Step D: This step involves the intramolecular cycloaddition of the aziridine to the tethered alkene through a thermally accessible azomethine ylide intermediate.
Step E: This step involves the reduction of the amide to an amine via standard reduction conditions employing DIBAL-H.
Step F: This step involves the removal of the benzylic protecting group using standard palladium conditions under a hydrogen atmosphere.
The process described in Scheme 1 utilizes expensive chiral auxiliary (R-naphthylethylamine or S-naphthylethyl-amine) followed by tedious chromatographic purification of diastereoisomers.
It is an object of this invention to provide a simplified reaction to make the compounds of formula (I) efficiently and in high yields.
It is a further object of this invention to make compounds of formula (I) that are optically pure (>98%).
Summary of the Invention
This invention provides more practical and economical processes for the manufacture of 6- phenethyl-octahydro-pyrrolo[2,3-c]pyridine and related compounds of formula (I):
Figure imgf000005_0001
The compounds of formula I are key intermediates for the preparation of dipeptide amides of formula(ll):
Figure imgf000005_0002
wherein UR5 are compounds of formula (I) which attach to the backbone of formula (II) via the nitrogen in the pyrrolo ring. Compounds of formula (II) can be used for treatment of proliferative diseases.
Detailed Description of the Invention
This invention discloses efficient processes for the synthesis of 6-phenethyl- octahydro-pyrrolo[2,3-c]pyridine and related compounds of formula (I).
Figure imgf000005_0003
which are key intermediates for the preparation of dipeptide amides of formula (M):
Figure imgf000005_0004
wherein R1 is H; C1-C4 alkyl; C1-C4 alkenyl; C1-C4 alkynyl or cycloalkyl which are unsubstituted or substituted;
R2 is H; CrC4alkyl; C1-C4 alkenyl; C1-C4 alkynyl or cycloalkyl which are unsubstituted or substituted;
R3 is H; -CF3; -C2F5; C1-C4 alkyl; C1-C4 alkenyl; C1-C4 alkynyl; -CH2-Z or R2 and R3 together with the nitrogen form a het ring;
Z is H; -OH; F; Cl; -CH3; -CF3; -CH2CI; -CH2F Or -CH2OH;
R4 is C1-C16 straight or branched alkyl; C1-C16 alkenyl; C1-C16 alkynyl; or -C3-C10 cycloalkyl; - (CH2)^6-Z1; -(CH2)o-6-aryl; and -(CH2)0.6-het, wherein alkyl, cycloalkyl and phenyl are unsubstituted or substituted;
Z1 is -N(R8)-C(O)-CrC10alkyl; -N(R8)-C(O)-(CH2)1-6-C3-C7cycloalkyl; -N(R8)-C(O)-(CH2)0.6- phenyl; -N(R8)-C(O)-(CH2)1.6-het; -C(O)-N(R9)(R10); -C(O)-O-CrC10alkyl; -C(O)-O-(CH2)1-6- C3-C7cycloalkyl; -C(O)-O-(CH2)0.6-phenyl; -C(O)-O-(CH2)1-6-het; -O-C(O)-C1-C10alkyl; -O- C(O)-(CH2)1-6-C3-C7cycloalkyl; -O-C(O)-(CH2)0.6-phenyl; -O-C(O)-(CH2)1-6-het, wherein alkyl, cycloalkyl and phenyl are unsubstituted or substituted;
het is a 5-7 membered heterocyclic ring containing 1- 4 heteroatoms selected from N, O and S, or an 8-12 membered fused ring system including at least one 5-7 membered heterocyclic ring containing 1, 2 or 3 heteroatoms selected from N, O, and S, which heterocyclic ring or fused ring system is unsubstituted or substituted on a carbon or nitrogen atom;
R8 is H, -CH3, -CF3 , -CH2OH or -CH2CI;
R9 and Ri0 are each independently H; CrC4alkyl; C3-C7cycloalkyl; -(CH2)i.6-C3-C7cycloalkyl; - (CH2)0-6-phenyl; wherein alkyl, cycloalkyl and phenyl are unsubstituted or substituted, or R9 and R1O together with the nitrogen form het;
R5 is (CH2)2-phenyl or R5 is a residue of an amino acid
U is a as shown in structure (III):
Figure imgf000007_0001
wherein
n = 0-5;
Ra and Rb are independently C0-2 alkyl wherein one or more of the carbon atoms in the alkyl chain may be replaced by a heteroatom selected from N, and where the alkyl may be unsubstituted or substituted;
Rd is -Re - Q - (Rf)p(Rg)q;
Rc is H or Rc and Rd together form cycloalkyl or het; where if Rd and Reform a cycloalkyl or het, R5 is attached to the formed ring at a N atom;
p and q are independently 0 or 1 ;
Re is C1-2 alkyl, or alkylidene, and Re may be unsubstituted or substituted;
Q is N;
Rf and Rg are each independently H; -CrC2 alkyl; -(CH2)i-6-het; -; or R9 and Rf form a ring selected from het ;
The general terms used hereinbefore and hereinafter preferably have within the context of this disclosure the following meanings, unless otherwise indicated:
"Het" refers heterocyclic rings and fused rings containing non-aromatic heterocyclic rings. "Het" is a 5-7 membered heterocyclic ring containing a heteroatom N1 or an 8-12 membered fused ring system including at least one 5-7 membered heterocyclic ring containing a heteroatom N. Unless otherwise specified "alkyl" includes straight or branched chain alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl and branched pentyl, n-hexyl and branched hexyl, and the like. .
A "cycloalkyl" group means C3 to C10cycloalkyl having 3 to 8 ring carbon atoms and may be, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl. Preferably, cycloalkyl is cycloheptyl.
Unsubstituted is intended to mean that hydrogen is the only substituent.
The previous synthesis of compounds (I) described in Scheme 1 utilizes microwave or autoclave conditions for the cycloaddition reactions leading to the cis-fused bicyclic system. The current process utilizes a mixture of triethoxyalkylsilane (DW-therm) as a solvent for this key cycloaddition reaction. As such the reactions are easily scalable and no special equipment is needed.
In one embodiment of the present invention, the chiral auxiliary (S)-naphthylethylamine is replaced by (f?)-naphthylethylamine and this results in easy chromatographic separation of the desired diastereoisomer as it eluted earlier than the undesired one.
In another embodiment, the expensive chiral auxiliary is replaced with the inexpensive benzylamine and the tedious chromatography step is replaced by a simplified resolution method.
The general reaction scheme of the current invention can be illustrated as follows:
Scheme 2
Figure imgf000009_0001
(I)
The resolution of the diastereomeric mixture produced in Scheme 2 above can be accomplished as shown below.
Scheme 3
Figure imgf000010_0001
1 : 1 Diastreomeric mixture s used herein, the designation:
Figure imgf000010_0002
racemic
refers to the 2 enantionmaers:
Figure imgf000010_0003
The general route for resolution of the isomers is shown in Scheme 4 below. This embodiment utilizes a resolution method produces compounds (I) in high yields.
Scheme 4
Figure imgf000011_0001
(I)
The procedures described in Scheme 4 above does not utilize the expensive chiral auxiliary (R-naphthylethylamine or S-naphthylethylamine) which is used in the procedures described in Schemes 1 and 2. Further, this preferred procedure eliminates the need of a tedious chromatographic purification of diastereoisomers. The key step in this approach is the resolution of the racemic bycycilc amine using (+)-dibenzoyl-D-tartaric acid which results in the isolation of the desired enantiomer in 90% (45% by weight) yield and in >98% optical purity in a single recrystallization.
The above schemes show dibenzoyl-D-tartaric acid as the resolving agent. However other chiral acids may be used as resolving agents, incuding those selected from 0,0'- diacetyltartaric acid, O,0'-diacroyltartaric acid, O.O'-dibenzoyltartaric acid, O1O'- dicyclohexylacetyltartaric acid, O.O'-dihexahydrobenzoyltartaric acid, O1O'- dimethylacroyltartaric acid, methyl hydrogen diacetyltartaric acid, or any other derivatives of tartaric acid.
The following examples more particularly illustrate the present invention, but do not limit the invention in any way.
Example 1 Preparation of 6-phenethyl-octahydro-pyrrolo[2,3-c]pyridine (A7)
Figure imgf000012_0001
Step 1 : A1 + A2 → A3
Figure imgf000012_0002
A1 A2 A3
Into a 12-liter, 4-neck flask equipped with a mechanical stirrer, a thermometer and an addition funnel are charged phenethylamine A2 (2 kg, 16.7 mol), potassium carbonate (766 g, 5.6 mol, 325 mesh), and acetonitrile (8 L) under nitrogen atmosphere. 4-Bromo-1-butene A1 (576 g, 5 mol) is added slowly at 20-25 0C over a period of 30 min. After the addition, the mixture is heated to 50 0C and stirred for an additional 3 h. The mixture is cooled to rt and stirred for an additional 12 h. The stirrer is stopped and any solid is allowed to settle. The supernatant (organic solution) is separated from the solid by siphoning. The remaining solid is filtered through a pad of celite, which is rinsed with acetonitrile (1 L). The organic solutions containing A3 are combined and evaporated under vacuum. The remaining concentrate is distilled under high vacuum to remove excess phenethylamine until its content in the pot residue is 1% or less. The remaining oil, compound A3, can be used as is. 1H NMR (500 MHz, CDCI3) δ 7.20-7.35 (m, 5H), 5.79 (m,1H) 5.00 - 5.10 (m, 2H), 2.92 (m, 2H), 2.84 (t, J = 6.8 Hz, 2H), 2.73 (t, J = 6.8 Hz, 2H), 2.27 (m, 2H).
Step 2: M3c + M3b → M3a
Figure imgf000013_0001
M3c M3b M3a
Into a 22-liter, 4-neck flask equipped with a mechanical stirrer, a thermometer, and an addition funnel are charged (R)-(+)-1-(1-naphthyl)ethylamine M3b (823 g, 4.8 mol) and acetonitrile (12.5 L) under nitrogen atmosphere. To this solution, potassium carbonate (1.33 kg, 9.6 mol) and 2,3-dibromopropionate M3c (1.42 kg, 5.8 mol) are added. The mixture is heated to 60 0C and stirred for an additional 2h. The mixture is cooled to rt and stirred for another 16h. Any solid is removed by filtration. The filtrate is concentrated under vacuum to obtain an oily residue. The oil is dissolved into terf-butyl methyl ether (2L) and hexane (1L), filtered through a pad of celite, and concentrated under vacuum to yield a brown oil (1.52 kg). The oil is purified by chromatography (silica gel; ethyl acetate/heptane 35:65) to obtain product M3a as an oil (1.18 kg, 96% yield): 1H NMR (500 MHz, CDCI3) δ 7.75 - 8.05 (m, 4H), 7.50 (m, 3H), 3.84 (s, 1.2 H), 3.72 (s, 1.8 H), 3.35 (m, 1 H), 2.50 (s, 0.6 H), 2.37 (m, 0.4 H), 2.25 (s, 0.4 H), 2.10 (m, 0.6 H), 1.95 (d, J = 6.4 Hz, 0.6 H), 1.60 - 1.70 (m, 3.4 H). Step 3: A3 → A4
Figure imgf000014_0001
Into a 22-liter, 4-neck flask equipped with a mechanical stirrer, a thermometer, and an addition funnel are charged M3a (1.11 kg, 4.35 mol) under nitrogen atmosphere. To the solution, potassium trimethylsilanolate (558 g, 4.35 mol) is added over a period of 20 min. After the addition, the mixture is stirred at rt for an additional 16 h. The mixture is concentrated under vacuum at 30 0C to give an oily residue. The oil is dissolved in dichloromethane (11 L) and cooled to 0 0C. Pivaloyl chloride (551 g, 4.6 mol) is added slowly and the mixture is warmed to rt, and stirred for an additional 1h. The mixture is cooled to 0 - 5 0C and compound A3 (800 g, 4.57 mol) is added. The mixture is warmed to rt and stirred for an additional 16 h. An aqueous solution of 1N NaOH (5 L) is added. The organic layer is separated, dried over MgSO4, and concentrated under vacuum at 30 0C to obtain compound A4 an oil (1.97 kg), which will be used for the next step without further purification.
Step 4: A4 → A5
Figure imgf000014_0002
Into a 2-liter, 4-neck flask equipped with a mechanical stirrer, a thermometer, and an addition funnel is charged DW-therm (900 g, a mixture of triethoxyalkylsilane, purchased from Huber) under nitrogen atmosphere. The solvent is heated to 240 0C. A solution of amide A4 (443 g, 1.1 mol) in DW-therm (400 g) is added over a period of 45 min, maintaining the batch temperature at 240 0C. After the addition, the mixture is stirred for an additional 20 min. The mixture is cooled to rt and allowed to settle into a two-phase solution. The thick bottom layer is separated and purified by chromatography (silica gel; EtOAc/heptane/ diethylamine 40:60:1) to isolate the first crop of product A5 as an solid. The upper layer is concentrated under vacuum at 60 - 70 °C/0.5 mmHg until small amount of DW-therm is present. The residual oil is purified by chromatography (silica gel; EtOAc/heptane/diethylamine 40:60:1) to isolate the second crop of product A5. Both crops of A5 are combined and recrystallized from a mixture of terf-butyl methyl ether and heptane to afford A5 as a solid: m.p. 103 - 1060C. 1H NMR (500 MHz, CDCI3) δ 8.36 (m, 1H), 7.80 (m, 1H), 7.72 (d, J = 8.2 Hz, 1H), 7.47 (d, J = 7.3 Hz, 1 H), 7.40 (m, 3H), 7.28 (m, 4H), 7.20 (m, 1 H), 5.36 (q, J = 6.7 Hz, 1 H), 3.76 (m, 1 H), 3.65 (m, 1 H), 3.51 (d, J = 8.2 Hz, 1 H), 3.35 (m, 1 H), 2.92 - 3.05 (m, 3H), 2.45 - 2.55 (m, 2H), 2.22 (m, 1 H), 1.65 - 1.80 (m, 2H), 1.57 (d, J = 6.7 Hz, 3H), 1.53 (m, 1H), 1.27 (m, 1H). 13C NMR (125 MHz, CDCI3) δ 170.0, 140.3, 139.7, 134.4, 132.9, 129.3, 129.0, 128.6, 128.7, 126.8, 125.7, 125.65, 125.61 , 125.27, 124.0, 61.9, 52.1, 50.3, 45.6, 4.6, 36.7, 34.6, 29.6, 28.9, 9.5.
Step 5: A5 -→ A6
Figure imgf000015_0001
Into a 3-liter, 4-neck flask equipped with a mechanical stirrer, a thermometer, and an addition funnel are charged compound A5 (40 g, 0.1 mol) and toluene (600 ml_) under nitrogen atmosphere. The solution is cooled to -70 0C. A solution of 1.5M DIBAL in toluene (200 mL, 0.3 mol) is added slowly, maintaining the batch temperature at - 70 0C. The mixture is warmed to rt over a period of 45 min and stirred for an additional 2 h. Ethyl acetate (200 mL) is added, maintaining the batch temperature at 20 - 25 0C. A saturated aqueous solution of NaHCO3 (100 mL) is added, keeping the batch temperature at 20 - 35 0C. After the addition, the batch is stirred at rt for an additional 1h. Any white solid is removed by filtration and rinsed with EtOAc. The combined filtrate is ished with 15% aqueous NaCI solution and concentrated under vacuum at 35 0C to yield an oil (44.3 g). The oil is purified by chromatography (silica gel; EtOAc/heptane/ diethylamine 80:20:1) to obtain product A6 as an oil (36.5 g, 95% yield): 1H NMR (500 MHz, CDCI3) δ 8.62.(s, 1H), 7.85 (d, J = 8.8 Hz, 1 H), 7.75 (d, J = 7.9 Hz, 1 H), 7.62 (s, 1 H), 7.32 - 7.52 (m, 3H), 7.10 - 7.32 (m, 5H), 4.56 (m, 1 H), 3.15 (s, 1 H), 2.48 - 2.85 (m, 8H), 2.25 (m, 3H), 1.65 - 1.90 (m, 4H), 1.55 (d, J = 6.1 Hz, 3H).
Step 6: A6 → A7
Figure imgf000016_0001
Into a 2.5-liter Parr bottle are charged 20% Pd(OH)2 on carbon (11.2 g, 50% wet) under nitrogen atmosphere. A solution of compound A6 (56 g, 0.15 mol) in methanol (1 L) is added. The mixture is hydrogenated at 50 psi for 16 h until all A6 is consumed. The mixture is filtered through a pad of celite under nitrogen atmosphere. The filtrate is concentrated under vacuum at 35 0C to give an oil. The oil containing A7 and the by-product is dissolved into ethyl acetate. A solution of 6N HCI in IPA (27 ml_) is diluted with EtOAc (60 mL) and added to the solution containing A7 over a period of 40 min at 18 - 27 0C. After the addition, the mixture is cooled to 0 0C and stirred for an additional 1 h. Any solid is collected by filtration to obtain A7 hydrochloride salt as a white solid (33 g, 82%): m.p. = 172 - 178 0C. 1H NMR (500 MHz, CDCI3) δ 7.12 - 7.32 (m, 5H), 3.50 (s, 1H), 3.15 - 3.35 (m, 2H), 2.45 - 2.95 (m, 8H), 2.20 (s, 2H), 1.95 (m, 1 H), 1.70 (m, 2H), 1.45 (s, 1H). By treating the hydrochloride salt with aqueous 1N NaOH solution, the free base of A7 is obtained as an oil: 1H NMR (500 MHz, CDCI3) 57.15 - 7.35 (m, 5H), 3.05 (m, 1 H), 2.96 (qAB, J = 8.2, 4.0 Hz, 1 H), 2.87 (m, 2H), 2.70 (m, 2H), 2.60 (m, 1 H), 2.49 (m, 2H), 2.40 (bs, 1H), 2.30 (dd, J = 11.6, 3.7 Hz, 1H), 2.02 (td, J = 11.0, 3.0 Hz, 1 H), 1.88 (m, 1 H), 1.77 (m, 1 H), 1.52 (m, 2H), 1.36 (m, 1 H). 13C NMR (125 Hz, CDCI3) δ 141.0, 129.1, 128.7, 126.3, 60.9, 58.6, 55.0, 53.0, 44.9, 36.6, 34.1, 31.9, 27.8. Rotation: α25 Na = -11.5° [c 9.57 mg/1 mL CH3CN].
Example 2 Preparation of 6-phenethyl-octahydro-pyrrolo[2,3-c]pyridine (A7)
I)KOTMS 2)TMACI
Figure imgf000018_0001
Figure imgf000018_0003
Figure imgf000018_0002
9 (racemic)
8 (racemic)
Pd/C
(+)-dibenzoyl-D- . (+)-dibenzoyl-D- tartaric acid
Figure imgf000018_0004
tartaric acid
Figure imgf000018_0005
10 (racemic) 11 (optically enriched salt)
Figure imgf000018_0006
A7 (ee > 98%)
Step i: Compound (A3)
A 1-L flask is charged with 2-phenylethylamine A2 (47.62 g, 393 mmol), K2CO3 (163.7 g, 1.184 mol), 4-bromo-1-butene A1 (35.5 g, 263 mmol), NaI ( 177 g, 1.184 mol) and DMF (500 ml_). The reaction mixture is heated to 100 0C and hold at this temperature for 22 h. Cool the reaction mixture to 20 0C , add water (700 ml_) and TBME (700 mL). The organic layer is washed with water, dried over MgSO4 and concentrated to give yellow oil which is further purified by distillation under reduced pressure to give 35.1 g of A3 in 76% yield.
Step 2: Compound (6)
A solution of M3c (25.27 g, 103 mmol) in methanol (75 ml_) is slowly added to a pre-cooled solution of benzyl amine 4 ( 38.37 g, 360 mmol) in methanol (250 mL) at 5-6 0C. The reaction mixture is warmed to 20-25 0C and maintained at this temperature for 18 h. The reaction mixture is concentrated and TBME (500 mL) and water (500 mL) are added. The organic layer is washed with water, dried over MgSO4 and concentrated to give yellow oil. The crude is further purified with column chromatography on silica gel (EtOAc/Hexanes= 1/1) to give 15.43 g of 6 in 78% yield.
Step 3: Compound (7)
KOTMS (6.38 g, 49.75 mmol) is added to a solution of 6 (9.51 g, 49.75 mmol) in THF (20OmL). The mixture is stirred overnight at room temperature. The mixture is concentrated and the residue dissolved in dichloromethane (20OmL) and cooled to 0 0C. Trimethylacetyl chloride (5.94 g, 49.25 mmol) is added slowly and the mixture is warmed to room temperature over 2 hours. The mixture is cooled to -78 0C, 3 (8.63 g, 49.24) is added and stirred at -78 0C for 1.5 hours. Saturated sodium bicarbonate (10OmL) is added. The mixture is extracted with EtOAc (4x10OmL). The organic extracts are combined, dried and concentrated under vacuum. The residue is purified by flash chromatography (silica gel; Hexane/EtOAc 1:8) to provide 12.5 g (76%) of the title compound 7.
Step 4: Compound (8)
A solution of 7 (10.7 g, 32 mmol) in DW-Therm Transfer (8 mL) is added within 15 min to a flask containing DW-Therm Transfer fluid ( 10 mL) at 240 0C and this temperature maintained for 30 min. The DW-Therm is distilled under vacuum and the residue is purified by flash chromatography on silica gel (EtOAc/Hexanes) to give 7.50 g of the racemic compound 8 in 70% yield.
Step 5: Compound (9)
At 20 0C, 30 mmol of LAH (1M in THF) is slowly added to a solution of 9.94 g (30 mmol) of 8 in THF (220 mL), then 60 °C for 3 h. While stirring, 1.1 g of water is added, then 1.1 mL of 15% NaOH (aq), stir, and then 3.4 mL of water is added. The suspension is stirred for 20 min, then filtered through a celite bed. The filtrate is washed with water two times, then brine, then the aqueous layers are combined and extracted with TBME. The organic layer is dried with MgSO4, and the solvents removed. The product, 8.79 g 9,is obtained as clear amber color oil. Yield: 8.79 g (92 %). HPLC purity 96.7 %.
Step 6: Compound (10)
8.65 g (27 mmol) of 9, 1.1 g of 10% Pd /C (50% wet), and 250 mL of MeOH are stirred under 60 psi hydrogen at RT overnight. The mixture is filtered and then concentrated to obtain 6.28 g of 10 as a yellow oil. Yield: 6.28 g (84%).
Step 7: Compound (11 )
16.10 g (70 mol) of 10 is dissolved in a solution of 85 mL of 2-propanol and 127 mL of 200 proof ethanol. To the clear solution is slowly added a solution of 25.08 g of (÷)-dibenzoyl-D- tartaric acid in 84 mL of 200 proof ethanol. 425 mL of toluene is added and stirred for 15 hours at room temperature. The solids are filtered, and the cake rinsed with 30 mL of a mixed solvents (2-propanol : ethanol : toluene = 1 : 2.5 : 5.0 [v/v/v]). Dry at 50 0C in a vacuum oven. Obtain 21.6 g of 11 as white crystals. Yield: 18.95 g (92%); HPLC Chemical purity: > 99%; Optical purity: > 99%; Rotation: α25 Na = +69.4 ° [c 10.3 mg/ in 1 mL CH3CN/H2O (1 / 1)].
Step 8: Compound A7
18.07 g of 11 is mixed and stirred with 90 mL of 1N sodium hydroxide solution, then extracted with methyl t-butyl ether. The organic layer is washed with water, dry with MgSO4, filtered, and then concentrated to a minimum volume. 6.89 g of A7 identical in all respects with the one described earlier is obtained. Yield: 6.89 g (99%); HPLC: Chemical purity: > 99%; Optical purity: > 99%; Rotation: α25 Na = -11.5° [c 9.57 mg/1 mL CH3CN] 1H NMR (500 MHz, CDCI3) δ 7.15 - 7.35 (m, 5H), 3.05 (m, 1H), 2.96 (qAB, J = 8.2, 4.0 Hz, 1H), 2.87 (m, 2H), 2.70 (m, 2H), 2.60 (m, 1H), 2.49 (m, 2H), 2.40 (bs, 1H), 2.30 (dd, J = 11.6, 3.7 Hz, 1H), 2.02 (td, J = 11.0, 3.0 Hz, 1H), 1.88 (m, 1 H), 1.77 (m, 1H), 1.52 (m, 2H), 1.36 (m, 1H). 13C NMR (125 Hz, CDCI3) δ 141.0, 129.1, 128.7, 126.3, 60.9, 58.6, 55.0, 53.0, 44.9, 36.6, 34.1, 31.9, 27.8. Abbreviations:
CH2CI2 methylene chloride
CH3CN acetonitrile
DIBAL diisobutylaluminium hydride
DIPEA diisopropylethylamine
DME ethylene glycol dimethyl ether
DMF N, Λ/-dimethylformamide
DTBB 4,4'-di-tert-butylbiphenyl
EtOAc ethyl acetate
HBTU O-benzyltriazol-1-yl-Λ/,Λ/,Λ/',Λ/-tetramethyluronium hexafluorophosphate
HOBt 1 -hydroxhbenzotriazole
HPLC high pressure liquid chromatography
KOTMS potassium trimethysilanoate.
MeOH methanol
MgSO4 magnesium sulfate
MnO2 manganese dioxide
Na2CO3 sodium carbonate
NaHCO3 sodium bicarbonate
NaOH sodium hydroxide rt room temperature
Tetrakis tetrakis(triphenylphosphine)palladium(0)
TFA trifluoroacetic acid
THF tetrahydrofuran

Claims

What is claimed is:
1. A process for preparing compounds of the formula I
Figure imgf000022_0001
(D comprising the following reaction
Figure imgf000022_0002
(I) wherein n is O, 1 or 2.
2. A process for preparing compounds of the formula (I)
Figure imgf000023_0001
comprising the following reaction
Figure imgf000023_0002
Figure imgf000023_0003
Figure imgf000023_0004
'
Figure imgf000023_0006
Figure imgf000023_0005
racemic racemic
(+)-dibenzoyl-D- tartaric acid
(+)-dibenzoyl-D-
Figure imgf000023_0007
Figure imgf000023_0008
racemic Optically enriched salt
NaOH
Figure imgf000023_0009
(I)
wherein n is 0, 1 or 2.
3. A process for preparing the compound of formula (A7)
Figure imgf000024_0001
A7
comprising the following reaction
Figure imgf000024_0002
(A7)
4. A process for preparing the compound of formula (A7)
Figure imgf000024_0003
A7
comprising the following reaction:
Figure imgf000025_0001
I)KOTMS 2)TMACI
Figure imgf000025_0003
Figure imgf000025_0004
racemic
Figure imgf000025_0005
Figure imgf000025_0006
Figure imgf000025_0002
racemic
Pd/C H,
zoyl-D- id
Figure imgf000025_0007
racemic
(optically enriched salt)
A7 (ee > 98%)
5. A process for preparing compounds of the formula I
Figure imgf000025_0009
comprising cycloaddition, with triethoxyalkylsilane (DW-Therm) as the solvent, of a compound of the formula:
Figure imgf000026_0001
wherein n is 0, 1 or 2.
6. A process according to claim 5 wherein n is 1.
7. A process for the resolution of racemates of formula (I1):
Figure imgf000026_0002
acem ic
(I1) comprising the following steps:
(chiral acid)
Figure imgf000026_0003
d salt racemic
Figure imgf000026_0004
optically pure (|) wherein the chiral acids used as resolving agents are selected from O.O'-diacstyitartaric acid, O,O!-diacroyltartaric acid, O,O'-dibenzoyltartaric acid, O,0j-dicyclohexylacetyltartaric acid, O.O'-dihexahydrobenzoyltartaric acid, O,O'-dimethylacroyltartaric acid, methyl hydrogen diacetyltartaric acid, or any other derivatives of tartaric acid.
8. A process for the resolution of racemates of formula (A71):
Figure imgf000027_0001
racemic (A71) comprising the steps of
(+)-dibenzoyl-D- tartaric acid (+)-dibenzoyl-D- tartaric acid
Figure imgf000027_0002
racemic Optically enriched salt
Figure imgf000027_0003
optically pure A7 wherein (+)-dibenzoyl-D-tartaric acid is the resolving agent.
PCT/US2006/012498 2005-04-06 2006-04-04 Processes to prepare 6-phenethyl-octahydro-pyrrolo [2 , 3-c] pyridine and related compounds WO2006107964A2 (en)

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CN112939849A (en) * 2019-12-11 2021-06-11 浙江新和成股份有限公司 (S, S) -2, 8-diazabicyclo [4.3.0] nonane intermediate and preparation method and application thereof

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005097791A1 (en) * 2004-04-07 2005-10-20 Novartis Ag Inhibitors of iap

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005097791A1 (en) * 2004-04-07 2005-10-20 Novartis Ag Inhibitors of iap

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
HENKE, B. R. ET AL.: "Intramolecular 1,3-Dipolar Cycloaddition of Stabilized Azomethine Ylides to Unactivated Dipolarophiles" J. ORG. CHEM., vol. 57, no. 26, 1992, pages 7056-7066, XP002401539 *

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CN112939849B (en) * 2019-12-11 2022-05-03 浙江新和成股份有限公司 (S, S) -2, 8-diazabicyclo [4.3.0] nonane intermediate and preparation method and application thereof

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