PROCESSES AND COMPOUNDS

Abstract

Useful processes of preparation and intermediates useful for the preparation of Compound 1, a selective estrogen receptor alpha (ER) modulator/degrader (SERM/SERD), having utility for the treatment of ER+ cancers including breast cancer are described.

Claims

1. A compound selected from (a), (b), (e), (f), and (g) ##STR00046##

2. A compound of claim 1 having formula (e) or (g) wherein said compound is present in an enantiomeric excess of >50%.

3. A compound of claim 1 having formula (e) or (g) wherein said compound is present in an enantiomeric excess of >60%.

4. A compound of claim 1 having formula (e) or (g) wherein said compound is present in an enantiomeric excess of >70%.

5. A compound of claim 1 having formula (e) or (g) wherein said compound is present in an enantiomeric excess of >80%.

6. A compound of claim 1 having formula (e) or (g) wherein said compound is present in an enantiomeric excess of >90%.

7. A compound of claim 1 having formula (e) or (g) wherein said compound is present in an enantiomeric excess of >95%.

8. A compound of claim 1 having formula (e) or (g) wherein said compound is present in an enantiomeric excess of >98%.

9. A compound of claim 1 having formula (e) or (g) wherein said compound is present in an enantiomeric excess of >99%.

10-65. (canceled)

66. The compound according to claim 1, wherein the compound is Compound (a): ##STR00047##

67. The compound according to claim 1, wherein the compound is Compound (b): ##STR00048##

68. The compound according to claim 1, wherein the compound is Compound (e): ##STR00049##

69. The compound according to claim 1, wherein the compound is Compound (f): ##STR00050##

70. The compound according to claim 1, wherein the compound is Compound (g): ##STR00051##

Description

DETAILED DESCRIPTION OF THE INVENTION

[0087] Compound 1 has demonstrated promising mixed activity as a selective estrogen receptor alpha (ER) modulator/degrader (SERM/SERD) against breast cancer, acting as a SERM at low doses and a SERD at high doses.

##STR00040##

[0088] Due to the interest in further development of Compound 1, larger quantities derived from innovative and efficient syntheses are needed for both preclinical and clinical studies with the eventual hope that the compound will be approved for commercial use, after which even much larger amounts will need to be produced. Accordingly, new and more efficient syntheses are needed. The present disclosure provides new and unexpectedly improved syntheses over the prior art disclosures (see e.g., U.S. Pat. No. 7,612,114).

[0089] The present disclosure provides both general procedures as well as specific examples demonstrating the efficacy of the described procedures.

[0090] As used herein, the terms below have the following definitions unless stated otherwise.

[0091] Compound 1 or RAD1901 has the following structure:

##STR00041## [0092] including salts, solvates (e.g. hydrate), and prodrugs thereof. In some embodiments, the pharmaceutically acceptable salt of Compound 1 is Compound 1 dihydrochloride or Compound 1 bis hydrochloride (.Math.2HCl) salt having the following structure:

##STR00042##

[0093] A halogen atom is a fluorine, chlorine, bromine or iodine.

[0094] An alkyl group is a linear or branched chain, monovalent saturated hydrocarbon radical optionally substituted with up to five independently selected halogen atoms, hydroxyl groups (OH), methyl, ethyl or propyl ether groups (OMe, OEt, OPr or OiPr), cyano groups (CN) or NO.sub.2 groups. For example, a C.sub.1-5 alkyl group includes -methyl, -ethyl, -isopropyl, -2-chloro-3-hydroxylbutyl, -2-fluoro-4-nitro-pentyl, etc.

[0095] An aryl group is a monovalent aromatic hydrocarbon radical of 6-20 carbon atoms (C.sub.6-C.sub.20). Aryl includes such structures as phenyl, biphenyl, naphthyl, etc. Aryls can be optionally substituted with up to five substituents independently selected from -halogen, -C.sub.1-6 alkyl ethers, -hydroxyl, CN, C.sub.1-6 alkyl and NO.sub.2.

[0096] A heteroaryl group is a cyclic aromatic group containing between 4 and 9 carbon atoms and containing between 1 and 3 heteroatoms, such as nitrogen, oxygen or sulfur. Said heteroaryl group may be monocyclic or bicyclic. By way of non-limiting example said heteroaryl includes without limitation oxazole, pyridine, quinoline, pyran, pyrrole and the like. Further, said heteroaryl can be substituted with up to five substituents selected from -halogen, C.sub.1-6 alkyl ethers, -hydroxyl, CN, C.sub.1-6 alkyl and NO.sub.2.

[0097] Where terms are joined, as in, for example, C.sub.1-C.sub.8 alkylaryl, the definitions for the separate functions (e.g., C.sub.1-8 alkyl and aryl) are each as defined separately including, for example, substitutions and branching. Thus, a C.sub.1-8 alkylaryl could include an alkyl radical of 1-(3-chloro-nitrobutyl)-3-methylbenzene where the radical point of attachment is on the terminus of the butyl fragment as shown below:

##STR00043##

[0098] In the processes provided herein, reference is made to protecting groups, such as a phenol protecting group or an amino protecting group. When described accordingly, one of ordinary skill in the art will appreciate that the particular protecting group can be selected from protecting groups known to those of skill in the art and also protecting groups varying from those known to those of skill but understood to be logical extensions of those groups and understood or predicted to operate by the same mechanism and having similar properties to those most closely related to those known in the art. While not wishing to be bound by example, protecting groups useful for the processes outlined herein can be found in various textbooks and hereby incorporated by reference. For example, see Protective Groups in Organic Synthesis (Green (Wuts), Wiley Publishing), Protecting Groups in Organic Synthesis: (Postgraduate Chemistry Series) (Hanson, Wiley Publishing), Protecting Groups (Kocienski, Thieme Publishing).

[0099] An example of the processes described here is shown in Scheme 1 and described briefly below. The vinyl bromide exemplified by compound (a) can be converted to its boron derivative (a) (2-(6-(benzyloxy)-3,4-dihydronaphthalen-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane) and then coupled with (aa) (N-(2-bromo-5-methoxyphenyl)acetamide) in the presence of base to render the coupled compound (b) (N-(2-(6-(benzyloxy)-3,4-dihydronaphthalen-2-yl)-5-methoxyphenyl) acetamide in an overall yield of >70%. Compound (b) was then reduced with Pd(OH).sub.2/H.sub.2 which both reduced the double bond and debenzylated the phenol to render (c) which was subsequently de-acetylated to produce compound (d) with the yield over both steps (b to d) of >90%. Compound (d) is typically a 50:50 racemic mixture and the desired compound has the (R)-stereochemistry at the 6-position. In this regard, it has been discovered that forming the acid addition salt with the appropriate chiral acids (as described herein) followed by crystallizing the product can efficiently increase the enantio-purity of compound (e) and related derivatives. In the present example, a racemic mixture was treated with (+)-2,3-dibenzoyl-D-tartaric acid [(+)-DBTA, 0.5 eq.] and the desired salt crystallized out in >90% ee and >90% of the theoretical yield of the desired enantiomer. The next step is the reductive amination of compound (e) with benzaldehyde (f) wherein the Schiff base is formed first between the aldehyde (f) with the aniline (e), followed by reduction with NaBH(OAc).sub.3 and the yield of crude product >90%. The reaction reduces the Schiff base formed between the amine (e) and benzaldehyde (f) and surprisingly also ethylates the aniline to give the desired tertiary aniline. Not wishing to be bound by theory, it is believed that acetyl transfer and reduction from the NaBH(OAc).sub.3 reagent occurs. The product (g) was reduced with NaBH.sub.4/I.sub.2 which is believed to generate BH.sub.3 in situ followed by a reductive work up with Na.sub.2S.sub.2O.sub.3 and the product purified and treated with HCl (MeOH, EtOH and/or EtOAc) and the yield of the bis HCl salt of Compound 1 was >50%.

##STR00044## ##STR00045##

[0100] Step 1Preparation of N-(2-(6-(benzyloxy)-3,4-dihydronaphthalen-2-yl)-5-methoxyphenyl)acetamide (b).

[0101] A solution of (a, 1 eq.) and bis(pinacolato)diboron (1.3 eq.) were dissolved in 7 volumes of 1,2-dimethoxyethane (DME), treated with KOAc (3.1 eq.) and PdCl.sub.2(PPh.sub.3).sub.2 (2 mol %), and heated at 85 C. The reaction was then monitored for completion by HPLC. The solution was cooled to 20 C. and treated with 25 wt % KHCO.sub.3 (aqueous, 3 volumes) and 2-bromo-5-methoxyacetanilide (aa, 1 eq), then heated to 85 C. and monitored for completion by HPLC. The reaction was then cooled to 55 C. and the mixture filtered and the solids washed with DME. The water layer was separated off and the remaining organic layer cooled to 20 C. and diluted with 6.9 volumes of water. The mixture was then agitated for 1 hour and the formed solids filtered and washed with 3.1 volumes of water and the cake dried at 55 C. The combined solids were treated with 10 volumes of dichloromethane (DCM) and carbon (0.25 wt equivalents) and the resulting mixture was stirred and heated to reflux (approx. 40 C.) for 6 hours. The mixture was then cooled to 20 C., the solid filtered, and washed with 3 volumes of DCM. The resulting filtrate solution was concentrated to 3 volumes under vacuum at 45 C. and treated with 6 volumes of ethanol (EtOH) and concentrated under vacuum at 45 C. to 4.9 volumes. An additional 6 volumes of EtOH was added and the volume once again concentrated under vacuum at 45 C. to 4.9 volumes and 1 volume of EtOH added and cooled to 20 C. and the product collected by filtration and rinsed with 1 volume of EtOH and dried under N.sub.2 at 50 C. to provide (b) in >70% yield.

[0102] Step 2Preparation of (+/)N-(2-(6-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)-5-methoxypheny)acetamide (c)

[0103] A solution of (b) (1 eq.), Pd(OH).sub.2/C (0.1 weight equivalents), THF (7 volumes) and MeOH (7 volumes) was purged with N.sub.2 and then H.sub.2 at 20 C. The reaction mixture was agitated under 100 psi H.sub.2 for 12 hours at 20 C. and the reaction monitored for completion. After purging the reaction with N.sub.2 at 20 C., the reaction mixture was heated at 40 C. for 1 hour, filtered and rinsed with 1.5 volumes of THF and 1.5 volumes of MeOH. The solution was concentrated to 2.4 volumes under vacuum at 45 C. and treated with 12 volumes of EtOAc, concentrated to 2.4 volumes under vacuum at 45 C., treated again with 12 volumes of EtOAc and concentrated to 2.4 volumes under vacuum at 45 C. and treated with 3.3 volumes of EtOAc and the temperature adjusted to 20 C. and agitated at 20 C.1 hour, the product collected by filtration and washed with 1.4 volumes of EtOAc. The solid can be recrystallized in MeOH/EtOAc if desired and the product (c) dried at temperatures 50 C.

[0104] Step 3Preparation of (+/)6-(2-amino-4-methoxyphenyl)-5,6,7,8-tetrahydronapthalen-2-ol (d)

[0105] A solution of ((c), 1 eq.) in 9 volumes of MeOH and concentrated HCl (1.5 wt equivalents) was heated and agitated at reflux 16 hours (approx. 65 C.) and monitored for completion. The reaction was cooled to 35 C. and concentrated under vacuum at 45 C. to 3.8 volumes, charged with 3 volumes of 2-MeTHF and concentrated under vacuum at 45 C. to 3.8 volumes, charged with 3 volumes of 2-MeTHF and concentrated under vacuum at 45 C. to 3.8 volumes, charged with 12 volumes of 2-MeTHF then 10 volumes of 1 M NaOH followed by 1.5 weight equivalents of 25% KHCO.sub.3 while maintaining the internal temperatures at 35 C. The internal temperature was adjusted to 20 C. and stirred for 15 minutes. The pH was adjusted/maintained to between 8-10 using 1 M HCl or 1 M NaOH. The agitation was stopped and the aqueous layer separated out after settling and 1 volume of H.sub.2O added and the solution stirred 15 minutes and the aqueous layer removed after settling and one additional volume of H.sub.2O added and the aqueous layer separated out after settling. The organic layer was concentrated under vacuum to 3 volumes at 45 and the solution treated with 3 volumes of heptane and agitated for 12 hours at 20 C. The solids were collected by filtration and the filter cake rinsed with 2 volumes of heptane. The solvents were evaporated at 50 C. to provide the title compound (d) in a yield of >90%.

[0106] Step 4Preparation of compound (R)-6-(2-amino-4-methoxyphenyl)-5,6,7,8-tetrahydronapthalen-2-ol (e)

[0107] One equivalent of (d) in 14.2 volumes of MeCN and 4.8 volumes of DCM was heated to 40 C. To this was added (+)-2,3-dibenzoyl-D-tartaric acid [(+)-DBTA, 0.5 eq.] and heated to reflux (approximately 65 C.). The reactor was cooled to 50 C. for approximately 1 hour, cooled to 40 C. for approximately 1 hour and cooled to 25 C. for approximately 1 hour. The slurry was filtered and the filter cake washed with 2 volumes of DCM. The wet filter cake was refluxed (approximately 44 C.) in 8 volumes of DCM for 1 h. The solution was cooled to 25 C. at a rate of 15 C./h and stirred at 25 C. for 1 hour. The slurry was filtered and washed with 2 volumes of DCM and the cake was again slurried with 8 volumes of DCM for 1 hour at ambient temperature and then filtered and washed with 2 volumes of DCM and dried. (The chiral purity was assayed at this point, providing an enantiomeric excess of >90%).

[0108] A solution containing the (+)-DBTA salt, 15 volumes of water and 3 volumes of methanol was treated with 4.6 volumes of a 25% KHCO.sub.3 aqueous solution and agitated at 25 C. for 1 h. The solids were collected by filtration and rinsed with 4 volumes of water. The aqueous layer was adjusted to a pH of 8 using 25% KHCO.sub.3 as needed, and the resulting solids were collected by filtration. The filter cake was washed with 4 volumes of water. The combined solids were added to 4 volumes of water, the resulting slurry was stirred for 1 h, and the solids were then collected by filtration. The filter cake was washed with 4 volumes of water and 4 volumes of heptane and was dried at 50 C. to provide the title compound (R)-6-(2-amino-4-methoxyphenyl)-5,6,7,8-tetrahydronapthalen-2-ol (e). The yield was determined to be >90% and the ee was determined to be >90%.

[0109] Step 5-Preparation of (R)-N-ethyl-3-(4-((ethyl(2-(6-hydroxy-1,2,3,4-tetrahydronapthalen-2-yl)-5-methoxyphenyl)amino)methyl)propanamide (g)

[0110] A mixture containing 1 equivalent of compound (e) together with 1 wt equivalent of activated molecular sieves and anhydrous THF was agitated at ambient temperature for 2 hours. The mixture was filtered through THF-compacted celite and rinsed with 10 volumes of THF. The solution was charged with N-ethyl-2-(4-formylphenyl)acetamide (f) (1.2 eq.) and 7.5 volumes of heptane and DBTA (0.1%) and heated to reflux (approximately 65 C.). The mixture was atmospherically distilled to 10 volumes at reflux. The reaction was monitored for completion via TLC. 2.9 volumes of heptane and 7.1 volumes of THF were added and the reaction was atmospherically distilled to 10 volumes at reflux and monitored for completion by TLC. The solution was cooled to 20 C. and agitated for 5 hours to ensure that crystallization had occurred. The solid product was collected by filtration, rinsed with 2 volumes of heptane and dissolved in 40 volumes of anhydrous THF and treated with 4.5 equivalents of NaBH(OAc).sub.3. The mixture was heated to 50 C. for 16 hours and monitored by TLC. An additional 4.5 equivalents of NaBH(OAc).sub.3 was added (additional N-ethyl-2-(4-formylphenyl)acetamide (f) could be added at this point if the reaction was not complete). The reaction was cooled to 20 C. and quenched with 15 volumes of 3 M NaOH. The solution/mixture was agitated for 30 minutes and the pH adjusted to 8-9 with 9% aqueous NaHCO.sub.3 (approximately 14 volumes) if necessary. The aqueous layer was separated out and the organic layer concentrated to 5 volumes under vacuum at 45 C. The resulting solution was diluted with 10 volumes of EtOAc and concentrated to 5 volumes under vacuum at 45 C. The solution was treated with 10 volumes of EtOAc and 5 volumes of 5.6% NaCl solution, stirred and then allowed to settle and the aqueous layer removed. The mixture was dried with Na.sub.2SO.sub.4 (4 wt) and filtered and concentrated to 5 volumes under vacuum at 45 C., treated with 10 volumes of heptane and concentrated to 5 volumes under vacuum at 45 C., treated with 10 volumes of heptane and concentrated to 5 volumes under vacuum at 45 C. and treated with 10 volumes of heptane and concentrated to 5 volumes under vacuum at 45 C. The solution was then treated with 10 volumes of THF and dried under vacuum at 45 C. and treated again with 10 volumes of THF and dried to 5 volumes under vacuum at 45 C. and treated with 5 volumes of THF and residual heptane evaluated by GC (<4%) and the THE solution carried forward to the next reaction. The yield of the final product was determined to be >90%.

[0111] Step 6Preparation of (R)-6-(2-(ethylamino)ethyl)benzyl)amino)-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-ol (Compound 1)

[0112] A reactor was charged with 7 volumes of THF and 2.5 equivalents of NaBH.sub.4 and cooled to from 10 C. to 0 C. The solution was charged with the THE solution carried over from step 6 (1 equivalent of intermediate (g)) while maintaining the reactor temperature at 5 C. The solution was stirred with an internal temperature adjusted to 25 C. 1 Equivalent of I.sub.2 in 1 volume of THF was added to the solution while maintaining the temperature at 10 C. The mixture was agitated for 30 minutes at 10 C. then heated to reflux and stirred at reflux (approximately 66 C.) for at 4 hours and monitored by HPLC for completion. The reaction mixture was cooled to 5 C. and quenched with 0.5 volumes of concentrated HCl while maintaining the reaction mixture temperature of 10 C., and then treated with 15 volumes of water. The pH was checked and adjusted to less than 1.5 as needed. The solution was then heated to reflux and atmospherically distilled until the internal temperature reaches 80 C. The reaction mixture was cooled to 15-25 C., stirred for 6 hours and the solid isolated by filtration. The solid was charged back into the reactor along with 10 volumes of EtOAc and 5 volumes of 1 M NaOH and the mixture agitated for up to 30 minutes at 10-20 C. The pH was checked and adjusted to 8-9 as needed. The organic and aqueous layers were allowed to separate and the aqueous layer removed and washed with 10 volumes of EtOAc. The aqueous layer was removed and the combined organic layers were washed with 25 volumes of 5% sodium thiosulfate solution. The organic layer was washed with 410 volumes of 1% NaCl solution. The aqueous layer was removed and the organic layer concentrated to 3 volumes at an external temperature of up to 45 C. Three times, the residue was dissolved in 10 volumes of EtOH and concentrated to 3 volumes at 45 C. The solution was dried with Na.sub.2SO.sub.4 and filtered and the filtrate charged to a reactor where it was treated with 1 volume of EtOAc and stirred and charged with 3.3 M HCl in EtOH (1.4 volumes) and the mixture agitated at 15-25 C. for 2 hours and then concentrated to 4.6 volumes at 45 C. The solution was treated with 12.4 volumes of EtOAc and agitated at 15-25 C. for 2 hours to ensure that crystallization had occurred. The solids were collected by filtration and rinsed with 3.1 volumes of EtOAc. The filter cake was dried at 50 C. The material can be assayed for purity and recrystallized from MeOH/EtOAc if desired. The yield of the final product was >50% and the purity >90%. If desired, the product can be recrystallized from EtOH/EtOAc to generate a polymorphic form having good stability.