WO2010048138A1 - Synthesis of intermediates useful for the production of certain cgrp inhibitors and intermediates used in such synthesis - Google Patents

Abstract

A method for making the compound of the formula (I), (IV), (VI), (VII) and (VIII), wherein R¹ is C_-1-5-alkyl, C(O)-O benzyl, C(O)-O-tert.butyl or benzyl; and R² is C₁-C₆ alkyl.

Description

SYNTHESIS OF SUBSTITUTED BENZODIAZEPINES USEFUL AS INTERMEDIATES FOR THE PRODUCTION OF CERTAIN CGRP INHIBITORS

BACKGROUND OF THE INVENTION 5 1. TECHNICAL FIELD

The invention relates to a method for making a compound of the formula (I)

wherein R¹ is Ci-₅-alkyl, C(O)-O-benzyl, C(O)-O-ferf.butyl or benzyl. The invention also 10 relates to intermediates used in such synthesis.

2. BACKGROUND INFORMATION

Compounds of formula I are known, having been described as intermediates for the production of certain CGRP inhibitors in WO 2005092880 and the corresponding 15 US20050234067, WO2006100026 and the corresponding US20060252750 and in WO2008022962 and the corresponding US20080045705.

BRIEF SUMMARY OF THE INVENTION

The invention provides an improved method for making intermediate compounds of 20 formula I, and intermediate compounds to be used in such method.

DETAILED DESCRIPTION OF THE INVENTION

In the first step of the improved method for making the compound of formula I, the compound of the formula II

is reacted with a compound of the formula (III)

wherein R is Ci-C₆ alkyl, to yield an intermediate compound of the formula (IV)

wherein R² is as hereinbefore defined.

The reaction between the compounds of formulas II and III is typically preformed in the presence of a base in a suitable aprotic polar solvent such as N-methyl pyrrolidone (NMP), tetrahydrofuran (THF), methyl tetrahydrofuran (MeTHF), methyl tert-butyl ether (MTBE) and other common polar solvents with THF being preferred solvent. Examples of suitable bases for this reaction include potassium tert-butoxide (tBuOK), sodium tert-butoxide (t- BuONa,) sodium bis(trimethylsilyl)amide (NaHMDS), potassium bis(trimethylsilyl)amide (KHMDS), lithium bis(trimethylsilyl)amide (LHMDS),Potassium 3,7-dimethyl-3-octylate (KDMO), potassium hydride (KH), sodium hydride (NaH), Sodium isopropoxide, potassium isopropoxide, and lithium diisopropylamide (LDA), with tBuOK being a preferred base.

The intermediates of formula IV are novel and constitute part of the invention.

In the next process step, the intermediate of formula IV is reacted with a compound of the formula V

-?-

wherein R¹ is as hereinbefore defined, to yield a further intermediate of the formula VI

This reaction is carried out in the presence of a strong base such as, for example, lithium hexamethyldisilazide (LHMDS) in an inert organic solvent such as, for example, tetrahydrofuran (THF), at reduced temperature. The intermediate of formula VI is preferably isolated by quenching the reaction by addition of aqueous solution of weak base such as sodium bicarbonate (NaHCOs) then extraction of the product from the aqueous mixture with common organic solvents such as ethylacetate then removal of the solvents.

The intermediates of formula VI are novel and constitute part of the invention.

In the next process step, the intermediate of formula VI is caused to undergo elimination to provide a further intermediate of the formula VII.

wherein R¹ and R² are as hereinbefore defined.

The elimination step is conveniently carried out in ether solvent such as tetrahydrofurane (THF) by activating the hydroxyl group with methanesulfunylchloride (MsCl) for example in the presence of base such as l,8-diazabicyclo[5.4.0]undec-7-ene (DBU), followed by elimination of the formed intermediate with the base. Excess amount of the same base (DBU) in the reaction mixture provides both transformations to give the product of the formula VII. The product is conveniently isolated after quench of the reaction mixture with diluted acid (0.1 N) such as hydrochloric acid (HCl) then extracted with organic solvent such as ethylacetate (EtOAc).

The intermediates of formula VII are novel and constitute part of the invention.

In the next process step, the intermediate of formula VII is hydrolyzed, to yield a further intermediate of the formula VIII

wherein R¹ is as hereinbefore defined.

The hydrolysis may be carried out using lithium hydroxide or sodium hydroxide in aqueous methanol, acetone, tetrahydrofuran or the like. Typically the reaction is carried out at about room temperature to 50⁰C for about 2h to 18h. At the end of the reaction, the product is isolated. Isolation may be accomplished by adjusting the pH of the reaction mixture with diluted acid to reach acidic pH between 4-2 followed by extraction with an organic solvent such as ethyl acetate. The obtained product is then crystallized.

The intermediates of formula VIII are novel and constitute part of the invention.

In the final process step the intermediate of formula VIII is reduced by asymmetric hydrogenation to yield the final product of formula I. The asymmetric hydrogenation may be carried out using an enantiomerically pure chiral catalyst prepared from a transition metal such as Rhodium, Ruthenium or Iridium with a chiral mono- or bisphosphine ligand such as, for example, a Binap ligand, a DuPhos ligand, a Josiphos ligand, a Butiphane ligand, a Meobiphep ligand, a Mandyphos ligand, a Taniaphos ligand, a Walphos Ligand, a BIPI ligand, a Rophos ligand, a Binam ligand, a BoPhoz ligand, DIPAMP and Norphos, (R,R) Ph-BPE, catASium ®, CTH R xylylPhos, Ferrotane, Tunephos, PhanePhos, TangPhos or a DuanPhos ligand. The hydrogenation will typically be carried out under hydrogen pressure of 20-500 psi at a temperature in the range of 0⁰C to 150°C, preferably in alcohol and/or ether solvent for 1-24 hours.

The product of formula I is preferably isolated at this point. This is conveniently accomplished by removing the heavy metal by treating the reaction mixture with a metals scavenger followed by removal of the solvent to give the desired product of formula I in acceptable purity.

The compound of formula (I) may be further converted to a pharmacologically useful compound of formula (X)

wherein R ,R i.s selected from the group consisting of:

H₃C The conversion may be performed in the manner described in WO2008022962 and the corresponding US20080045705, which are incorporated herein by reference in their entirety. More particularly, the compound of formula (I) may be converted to a compound of formula (X) by first reacting it with a suitable amine to provide an intermediate of formula (IX)

wherein R¹ and R^R are as hereinbefore defined.

Deprotection of the intermediate compound of formula (IX) by standard methods, such as hydrogenation, treatment with trialkylsilyliodide or hydrolysis, provides the compound of formula (X).

In a similar way the enantiomer of compound of formula (I), may be converted to the corresponding final compound of formula (X')

by using the corresponding enantiomeric catalyst.

TERMS AND DEFINITIONS USED By the term "Ci_-alkyl" (including those which are part of other groups) are meant straight chained or branched alkyl groups with 1, 2, 3, 4 or 5 carbon atoms and by the term "Ci_₆- alkyl" are meant straight chained or branched alkyl groups with 1, 2, 3, 4, 5 or 6 carbon atoms. Examples include: methyl, ethyl, «-propyl, ώo-propyl, n-butyl, iso-butyl, tert.butyl, n-penty and n-hexyl. The following abbreviations may also optionally be used for the above-mentioned groups: Me, Et, «-Pr, /-Pr, «-Bu, /-Bu, f-Bu, etc. etc. Unless stated otherwise, the definition propyl includes all the possible isomeric forms of the group. Thus, for example, propyl includes «-propyl and ώo-propyl.

The following example will serve to further illustrate the invention.

Example 1

Step 1 : Preparation of 2-ethoxy-2-oxoethyl-4-(2-oxo-4,5-dihydro-lH- benzo[d][l,3]diazepin-3(2H)-yl)piperidine-l-carboxylate (4)

In a 250 mL round-bottomed flask ethyl glycolate (7.04 ml, 70.7 mmol) and 3-(1-(1H- imidazole-l-carbonyl)piperidin-4-yl)-4,5-dihydro-lH-benzo[d][l,3]diazepin-2(3H)-one (20 g, 58.9 mmol) were added in tetrahydrofuran (50 ml) and the reaction mixture was cooled to 0⁰C. Potassium tert-butoxide IM THF (70.7 ml, 70.7 mmol) was added. The reaction mixture was stirred while warming up to 22°C during 1 h, then stirred at 22°C for 18h and monitored by LC-MS. The reaction was quenched with saturated aqueous ammonium chloride (200ml) and EtOAc (300ml). The layers were separated and the organic layer was dried and concentrated under reduced pressure to give 2 Ig, 91% yield of 2-ethoxy-2-oxoethyl-4-(2-oxo-4,5-dihydro-lH-benzo[d][l,3]diazepin-3(2H)-yl)piperidine- 1-carboxylate.

¹H NMR (400 MHz, DMSOd₆) : 8.48 (s, IH), 7.05-7.00 (m, 3H), 6.81-6.76 (m, IH), 4.60 (s, 2H), 4.29-4.20 (m, IH), 4.14 (q, J=7.1Hz, 2H), 4.10-4.01 (m, 2H), 3.37-3.34 (m, 2H), 3.00-2.83 (m, 2H), 2.89-2.86 (m, 2H), 1.65-1.58 (m, 4H), 1.20 (t, J=7.1Hz, 3H).

Step 2: Preparation of l-(4-(benzyloxy)-3,5-dimethylphenyl)-3-ethoxy-l-hydroxy-3- oxopropan-2-yl-4-(2-oxo-4,5-dihydro-lH-benzo[d][l,3]diazepin-3(2H)-yl)piperidine-l- carboxylate (6)

In a 250 mL round-bottomed flask was added 2-ethoxy-2-oxoethyl-4-(2-oxo-4,5-dihydro- lH-benzo[d][l,3]diazepin-3(2H)-yl)piperidine-l-carboxylate (2) (4 g, 10.65 mmol) in tetrahydrofuran (100 ml) and the reaction mixture was cooled to -50⁰C. Lithium bis(trimethylsilyl)amide IM THF (23.44 ml, 23.44 mmol) was added and the reaction mixture was stirred at -50⁰C for 30 min. 4-(Benzyloxy)-3,5-dimethylbenzaldehyde (2.69 ml, 11.72 mmol) was then added and the reaction was stirred at -50⁰C for 45 min, then warmed up to -30⁰C over 30 min then hold at this temperature for Ih. The reaction was then quenched at -25°C by addition of NaHCOo saturated aqueous solution, extracted with EtOAc, dried on MgSθ4 and the crude product was obtained as a white solid.

Purification by column chromatography provided the product, l-(4-(benzyloxy)-3,5- dimethylphenyl)-3-ethoxy-l-hydroxy-3-oxopropan-2-yl-4-(2-oxo-4,5-dihydro-lH- benzo[d][l,3]diazepin-3(2H)-yl)piperidine-l-carboxylate as a white powder, 4.4 g, 57% yield.

¹H NMR (600 MHz, DMSOd₆) : 8.11 (s, IH), 7.48-7.46 (m, 2H), 7.39 (t, J=7.1Hz, 2H), 7.35 (d, J=7.1Hz, IH), 7.08-7.03 (m, 4H), 6.97 (d, J=7.3Hz, IH), 6.83-6.78 (m, IH), 5.51 (d, J=5.1Hz, IH), 4.97 (d, J=5.3Hz,lH), 4.88 (t, J=5.3Hz, IH), 4.81 (s, 2H), 4.25-4.21 (m, IH), 4.15-4.00 (m, 4H), 3.33-3.28 (m, 2H), 2.93-2.80 (m, 4H), 2.25 (s, 3H, 33), 2.24 (s, 3H), 1.68-1.40 (m, 4H), 1.20 (t, J=7.1Hz, 3H).

Step 3: Preparation of (E)-l-(4-(benzyloxy)-3,5-dimethylphenyl)-3-ethoxy-3-oxoprop-l- en-2-yl-4-(2-oxo-4,5-dihydro-lH-benzo[d][l,3]diazepin-3(2H)-yl)piperidine-l-carboxylate

(7).

In a 500 mL round-bottomed flask were added l-(4-(benzyloxy)phenyl)-3-ethoxy-l- hydroxy-3-oxopropan-2-yl-4-(2-oxo-4,5-dihydro-lH-benzo[d][l,3]diazepin-3(2H)- yl)piperidine-l-carboxylate (3) (8.8 g, 14.29 mmol) and DBU (21.54 ml, 143 mmol) in tetrahydrofuran (250 ml) to give a tan solution. Methanesulfonyl chloride (1.782 ml, 22.87 mmol) was added. The reaction was stirred and heated to 50⁰C for 5h (LCMS monitoring). After reaching room temp the reaction was quenched with 100 ml 0.1 N HCl and extracted with EtOAc (2x 100 ml). The organic layer was washed with NaHCOo saturated aqueous solution (2xl00ml). The organic layer was dried (MgSO^_.) and the solvent removed under reduced pressure to give product 4 as light tan foam. The product was purified using column chromatography to give 6.2g off-white solid in 71.9% yield.

¹H NMR (400 MHz, CDCl₃) : 7.51-7.46 (m, 2H), 7.45-7.30 (m, 5H), 7.20 (s, IH, 2), 7.15- 7.05 (m, 2H), 6.94-6.89 (m, IH), 6.76-6.72 (m,lH), 6.63 (s, IH), 4.84 (s, 2H), 4.59-4.31 (m, 3H), 4.33 (q, J=7.1Hz, 2H), 3.52-3.50 (m, 2H), 3.23-2.89 (m, 2H), 3.04-3.00 (m, 2H), 2.31 (s, 6H), 1.91-1.75 (m, 4H), 1.38 (t, J=7.1Hz, 3H).

Step 4 : Preparation of (E)-3-(4-(benzyloxy)-3,5-dimethylphenyl)-2-(4-(2-oxo-4,5-dihydro- lH-benzo[d][l,3]diazepin-3(2H)-yl)piperidine-l-carbonyloxy)acrylic acid (8).

(2-ethoxy-2-oxoethyl-4-(2-oxo-4,5-dihydro-lH-benzo[d][l,3]diazepin-3(2H> yl)piperidine-l-carboxylate (4) (4.2 g, 7.03 mmol), methanol (5 ml, 124 mmol) and tetrahydrofuran (100 ml, 1220 mmol) were added to a 250 ml round bottom reaction vessel which was cooled to 0⁰C. Lithium hydroxide hydrate (0.354 g, 8.43 mmol) dissolved in water (20 ml, 7.03 mmol) was added and the reaction was stirred at 22°C for 24h then concentrated to minimum volume under reduced pressure and the residue was treated with water 3ml and extracted with EtOAc (20ml). The aqueous layer was acidified with concentrated HCl to pH = 2 then extracted with EtOAc (2 x 20 ml). The product was precipitated from EtOAc to give 3.85g in 95% yield.

¹H NMR (400 MHz, DMSO-d₆) : 8.50 (s, IH), 7.50-7.46 (m, 2H), 7.43-7.33 (m, 5H), 7.10 (s, IH), 7.04-7.00 (m, 3H), 6.81-6.78 (m, IH), 4.83 (s, 2H), 4.38-4.22 (m, 2H), 4.10-4.08 (m, IH), 3.40-3.36 (m, 2H, 25), 3.20-2.93 (m, 2H), 2.90-2.88 (m, 2H), 2.26 (s, 6H, 33), 1.80-1.65 (m, 4H).

Step 5: Synthesis of desired enantiomer (R)-3-(4-(benzyloxy)-3,5-dimethylphenyl)-2-(4- (2-oxo-4,5-dihydro-lH-benzo[d][l,3]diazepin-3(2H)-yl)piperidine-l- carbonyloxy)propanoic acid (1).

To a 2 ml vial containing the ligand (R)-l-{(S)-2-[di(2-furyl)phosphino] ferrocenyl}ethylbis(2-methylphenyl)phosphine (Josiphos ligand J505-1) (8mol%), was added a solution of the precatalyst (4mol% chloro-l,5-cyclooctadiene iridium (I) dimmer) in 1 ml methanol-tetrahydrofuran (2: 1). After 10 min the catalyst solution was added to the reaction vial containing the starting material ((E)-3-(4-(benzyloxy)-3,5-dimethylphenyl)-2-

(4-(2-oxo-4,5-dihydro-lH-benzo[d][l,3]diazepin-3(2H)-yl)piperidine-l- carbonyloxy)acrylicacid (5) (40 mg, 0.07mmol) and the syringe was washed with extra solvent which was added to the reaction vessel to a total of 1.5 ml methanol- tetrahydrofuran (2: 1). All operations were conducted in the glove box under nitrogen. The reactor was sealed and pressurized to 500 psi hydrogen at 60⁰C under stirring for 7 h. The crude reaction mixture was analyzed by HPLC using chiral method. It indicated complete conversion of the starting material to 95% product with 94%ee of the desired product. The crude reaction mixture can be used in the next step without further purification or the product can be recrystallized from methanol to give a white powder.

Similarly, 76%ee was obtained with complete conversion using (2R,4R)-(+)-2,4- Bis(diphenylphosphino) pentane as the chiral ligand

Synthesis of desired enantiomer (S)-3-(4-(benzyloxy)-3,5-dimethylphenyl)-2-(4-(2-oxo- 4 , 5 -dihydro- 1 H-benzo [d] [ 1 , 3 ] diazepin-3 (2H) -yl)piperidine- 1 -c arbonyloxy)propanoic acid (6). To a 2 ml vial containing the ligand (lmg, 5mol%, RoPhos, (+)-l,2-bis[(2S,5S)-2,5- dimethyl-(3S,4S)-3,4-dihydroxyphospholano]benzene bis(trifluoromethanesulfonate)salt was added a solution of the precatalyst (1.3 mg, 5mol%,bis(norbornadiene)rhodium (I) tetrafluoroborate) in 1 ml methanol-tetrahydrofuran (2:1) . After 10 min the catalyst solution was added to the reaction vial containing the starting material ((E)-3-(4- (benzyloxy)-3,5-dimethylphenyl)-2-(4-(2-oxo-4,5-dihydro-lH-benzo[d][l,3]diazepin-

3(2H)-yl)piperidine-l-carbonyloxy)acrylicacid (5) (40 mg, 0.07mmol) and the syringe was washed with extra solvent which was added to the reaction vessel to a total of 1.5 ml methanol-tetrahydrofuran (2:1). All operations were conducted in the glove box under nitrogen. The reactor was sealed and pressurized to 400 psi hydrogen at 60⁰C under stirring for 16 h. The crude reaction mixture was analyzed by HPLC using chiral method. It indicated complete conversion of the starting material to 95% product with 98%ee of the undesired enantiomer and 5% decarboxylated product (%A). The crude reaction mixture can be used in the next step without further purification or the product can recrystallized from methanol to give a white powder.

Similarly, 87%ee was obtained with complete conversion using (2R,3R)-(+)-2,3- bis(diphenylphosphino)-bicyclo[2.2.1]hept-5-ene as Rh cyclooctadiene tetrafluoroborate complex (Norphos).

¹H NMR (600 MHz, DMSOd₆) : 12.52 (s, IH), 8.11 (s, IH), 7.48-7.45 (m, 2H), 7.39 (t, J=7.1Hz, 2H), 7.35 (d, J=7.1Hz, IH), 7.04-7.02 (m, 2H), 6.97 (d, J=7.5Hz, IH), 6.94-6.93 (m, 2H), 6.81-6.78 (m, IH), 5.01-4.99 (m, IH), 4.80 (s, 2H), 4.26-4.23 (m, IH), 4.09-4.03 (m, 2H), 3.33-3.31 (m, 2H), 3.06 (dd, J₁₌4.3Hz, J₂=14.3Hz, IH), 2.95 (dd, J₁₌8.5Hz, J₂=14.3Hz, IH), 2.90-2.81 (m, 4H), 2.23 (s, 6H), 1.62-1.46 (m, 4H).

Claims

WHAT IS CLAIMED IS:

1. A process for making a compound of the formula (I)

wherein R¹ is Ci-₅-alkyl, C(O)-O-benzyl, C(O)-O-ferf.butyl or benzyl, which process comprises: (a) reacting the compound of the formula II

with a compound of the formula (III)

wherein R² is Ci-C₆ alkyl, to yield a compound of the formula (IV)

wherein R^z is as hereinbefore defined; (b) reacting the intermediate of formula IV with a compound of the formula V

wherein R¹ is as hereinbefore defined, to yield a compound of the formula VI

wherein R¹ and R² are as hereinbefore defined;

(c) causing the compound of formula VI to undergo elimination, to yield a further compound of the formula VII

wherein R¹ and R² are as hereinbefore defined;

(d) hydrolyzing the compound of formula VII, to yield a further compound of the formula VIII

wherein R¹ is as hereinbefore defined; and

(e) reducing the compound of formula VIII by asymmetric hydrogenation to yield the final product of formula I.

2. The process according to claim 1 wherein R¹ is benzyl and R² is ethyl.

3. A compound of the formula

wherein R is Ci-C₆ alkyl.

4. The compound of formula IV according to claim 3 wherein R is ethyl.

5. A compound of the formula

wherein:

R » i¹ i ^•s Ci.5-alkyl, C(O)-O-benzyl, C(O)-O-ferf.butyl or benzyl; and R² is Ci-C₆ alkyl.

6. The compound of formula VI according to claim 5 wherein R¹ is benzyl and R² is ethyl.

7. A compound of the formula

wherein:

R¹ is Ci.₅-alkyl, C(O)-O-benzyl, C(O)-O-ferf.butyl or benzyl; and R >2^z i •s Ci-C₆ alkyl.

8. The compound of the formula VII according to claim 7 wherein: R¹ is benzyl; and R² is ethyl.

9. A compound of the formula

wherein R¹ is Ci_₅-alkyl, C(O)-O-benzyl, C(O)-O-tørt.butyl or benzyl.

10. The compound of the formula VIII according to claim 9 wherein R¹ is benzyl.

11. A process for making a compound of the formula X

wherein R >R i ^•s selected from the group consisting of:

which process comprises:

(a) reacting the compound of the formula II

with a compound of the formula (III)

wherein R² is Ci-C₆ alkyl, to yield a compound of the formula (IV)

wherein R is as hereinbefore defined; (b) reacting the intermediate of formula IV with a compound of the formula V

wherein R¹ is as hereinbefore defined, to yield a compound of the formula VI

wherein R¹ and R² are as hereinbefore defined;

(c) causing the compound of formula VI to undergo elimination, to yield a further compound of the formula VII

wherein R¹ and R² are as hereinbefore defined; (d) hydrolyzing the compound of formula VII, to yield a further compound of the formula VIII

wherein R¹ is as hereinbefore defined; (e) reducing the compound of formula VIII by asymmetric hydrogenation to yield a compound of the formula I

(f) reacting the compound of formula I with a secondary amine selected from the group consisting of

to yield a compound of the formula IX

wherein R¹ and R^R are as hereinbefore defined, and (g) removing the protecting group R¹, to yield the final product of formula X.

12. The process according to claim 11 wherein R¹ is benzyl and R² is ethyl.