US2010099898A1PendingUtilityA1
Processes and Intermediates For Preparing Benzyle Epoxides
Est. expiryApr 23, 2021(expired)· nominal 20-yr term from priority
Inventors:Michael R. Reeder
C07D 301/26C07D 303/36C07C 229/36
68
PatentIndex Score
0
Cited by
0
References
0
Claims
Abstract
Disclosed are intermediates and processes for preparing epoxides of the formula: where R and PROT are defined herein. These epoxides are useful as intermediates in the production of biologically active compounds, i.e., in the production of pharmaceutical agents.
Claims
exact text as granted — not AI-modified1 . A compound of the formula:
where
R is phenyl optionally substituted with 1, 2, 3, or 4 groups independently selected from:
(A) C 1 -C 6 alkyl optionally substituted with one, two or three substituents independently selected from C 1 -C 3 alkyl, halogen, hydroxy, thio, —NR 10 R 11 where R 10 and R 11 are independently hydrogen or C 1 -C 6 alkyl, cyano, trifluoromethyl, and C 1 -C 2 alkoxy,
(B) C 2 -C 6 alkenyl or C 2 -C 6 alkynyl,
(C) halogen, hydroxy, cyano, C 1 -C 6 alkoxy optionally substituted with 1, 2, or 3 fluoro,
(D) —NR 12 R 13 where at each occurrence R 12 and R 13 are the same or different and represent:
(a) —H,
(b) —C 1 -C 8 alkyl optionally substituted with one of:
(i) —OH,
(ii) —NH 2 ,
(iii) phenyl,
(c) —C 1 -C 8 alkyl optionally substituted with 1, 2, or 3 independently selected halogens,
(d) —C 3 -C 8 cycloalkyl, —(C 1 -C 2 alkyl)-(C 3 -C 8 cycloalkyl), —(C 1 -C 6 alkyl)—O—(C 1 -C 3 alkyl), —C 2 -C 6 alkenyl, —C 2 -C 6 alkynyl; and
(E) C 3 -C 7 cycloalkyl, —C(O) (C 1 -C 4 alkyl), —SO 2 NR 10 R 11 , —C(O)NR 10 R 11 , or —SO 2 (C 1 -C 4 alkyl);
R 1 is selected from:
(I) C 1 -C 6 alkyl optionally substituted with one halogen;
(II) —CH 2 —CH═CH 2 ;
(III) phenyl optionally substituted with one nitro, halogen, or cyano; and
(IV) benzyl optionally substituted on phenyl with nitro, halogen, or cyano; and
R 30 represents hydrogen or PROT, where PROT is a nitrogen protecting group.
2 . An ester of the formula (II)
R 1 is selected from:
(I) C 1 -C 6 alkyl optionally substituted with one halogen;
(II) —CH 2 —CH═CH 2 ;
(III) phenyl optionally substituted with one nitro, halogen, or cyano; and
(IV) benzyl optionally substituted on phenyl with nitro, halogen, or cyano; and
PROT is a nitrogen protecting group.
3 . An ester according to claim 1 where PROT is t-butoxycarbonyl.
4 . An ester according to claim 1 where PROT is benzyloxycarbonyl.
5 . An ester according to claim 1 where R 1 is C 1 -C 2 alkyl.
6 . An ester according to claim 5 where R 1 is C 1 alkyl.
7 . An ester according to claim 1 which is selected from the group consisting of
(2S)-2-[(tert-butoxycarbonyl)amino]-3-(3,5-difluorophenyl)propanoic acid methyl ester and methyl (2S)-2-[[(benzyloxy)carbonyl]amino]-3-(3,5- difluorophenyl) propanoate.
8 . A compound of the formula
where R 2 is:
chloro, bromo, or
—Si(R 21 ) 3 where each R 21 is independently
C 1 -C 5 alkyl,
—N(R 23 )(R 24 ) where R 23 and R 24 are the same or different and represent
C 1 -C 5 alkyl,
or where NR 23 R 24 represents piperidinyl, piperazinyl, or morpholinyl,
phenyl optionally substituted with 1, 2, or 3 of C 1 -C 2 alkyl, with the proviso that at least one of the R 21 groups is optionally substituted phenyl.
9 . A compound according to claim 8 where R 2 is —Cl.
10 . A compound according to claim 8 where R 2 is —Br.
11 . A compound according to claim 8 which is (2S, 3S)-3-amino-1-chloro-4-(3,5-difluorophenyl)butan-2-ol.
12 . A compound according of the formula:
13 . A compound according of the formula:
where
X 1 is —Cl, —Br or imidazolyl; and
PROT is a nitrogen protecting group.
14 . A compound according to claim 13 where PROT is t-butoxycarbonyl or benzyloxycarbonyl.
15 . A compound according to claim 13 where X 1 is —Cl.
16 . A compound (XI) according to claim 13 where the compound is t-butyl-(1S)-2-chloro-1-[3,5-difluorobenzyl]-2-oxoethylcarbamate.
17 . A compound of the formula:
where
PROT is a nitrogen protecting group; and
R 1 is selected from:
(I) C 1 -C 6 alkyl optionally substituted with one chloro;
(II) —CH 2 —CH═CH 2 ;
(III) phenyl optionally substituted with one nitro, halogen, or cyano; and
(IV) benzyl optionally substituted on phenyl with nitro, halogen, or cyano.
18 . A compound according to claim 17 where the PROT is t-butoxycarbonyl or benzyloxycarbonyl.
19 . A compound according to claim 17 where R 1 is C 1 -C 2 alkyl.
20 . A compound according to claim 19 where R 1 is C 1 alkyl.
21 . A compound according to claim 17 which is methyl (2Z)-2-[[(benzyloxy) carbonyl]-3-(3,5-difluorophenyl)-2-propenonate.
22 . A compound of the formula:
where
R 1 is selected from:
(I) C 1 -C 6 alkyl optionally substituted with one chloro;
(II) —CH 2 —CH═CH 2 ;
(III) phenyl optionally substituted with one nitro, halogen, or cyano; and
(IV) benzyl optionally substituted on phenyl with nitro, halogen, or cyano.
23 . A compound according to claim 22 where R 1 is C 1 -C 2 alkyl.
24 . A compound according to claim 23 where R 1 is C 1 alkyl.
25 . A compound according to claim 22 which is methyl (2S)-2-amino-3-(3,5-difluorophenyl)propanoate.
26 . A process for the preparation of an ester of the formula:
where
R 1 is selected from the group consisting of:
(I) C 1 -C 4 alkyl optionally substituted with one —Cl;
(II) —CH 2 —CH═CH 2 , and
(III) benzyl optionally substituted on phenyl with nitro, halogen, or cyano; and
PROT is a nitrogen protecting group, which process comprises:
(a) contacting a protected amino acid of the formula (I)
where PROT is as defined above, with a base and
(b) contacting the mixture of (a) with an alkylating agent of the formula
(a) X 4 -C 1 -C 4 alkyl optionally substituted with one of iodo, bromo, or chloro;
(a′) dimethylsulfate;
(b) X 4 —CH 2 —CH═CH 2 ,
(c) X 4 -benzyl where the phenyl ring is optionally substituted with nitro, halogen, cyano; and
X 4 is iodo, bromo, chloro, —O—tosylate, —O—mesylate or —O—triflate.
27 . A process according to claim 26 where PROT is t-butoxycarbonyl or benzyloxycarbonyl.
28 . A process according to claim 26 where the base is hydroxide, carbonate, bicarbonate, LDA, n-(C 1 -C 8 alkyl)lithium, LiHMDS, NaHMDS or KHMDS.
29 . A process according to claim 28 where the base is hydroxide, carbonate, or bicarbonate.
30 . A process according to claim 29 where the base is carbonate.
31 . A process according to claim 26 where the alkylating agent is dimethylsulfate, methyl iodide or methyl triflate.
32 . A process according to claim 31 where the alkylating agent is dimethylsulfate.
33 . A process according to claim 26 where when the base is LDA, n-(C 1 -C 8 alkyl)lithium, LiHMDS or KHDMS, and the mixture of (a) is cooled to a range of from about −78° to about 25° prior to the addition of the base.
34 . A process according to claim 33 where the mixture of (a) is cooled to a range of from about −20° to about 25° prior to the addition of the base.
35 . A process according to claim 26 where the mixture of (b) is heated from about 20° to about 50°.
36 . A process according to claim 26 where the ester (II) is (2S)-2-[(tert-butoxycarbonyl) amino)-3-(3,5-difluorophenyl)propanoic acid methyl ester.
37 . A process for the preparation of an ester of the formula:
where
R 1 is phenyl optionally substituted with one of nitro, halogen, or cyano; and
PROT is a nitrogen protecting group, which process comprises:
(1) contacting a protected amino acid of the formula (I)
where PROT is as defined above, with an activating agent
(2) contacting the mixture of (1) with a phenoxy compound of the formula
(d) HO—φ where —φ is optionally substituted with one:
(A) —NO 2 ,
(B) —F, —Cl, —Br, —I,
(C) —C≡N.
38 . A process according to claim 37 where PROT is t-butoxycarbonyl and benzyloxycarbonyl.
39 . A process according to claim 37 where the activating agent is CDI.
40 . A process according to claim 37 where the activating agent is DCC.
41 . A process for the preparation of a ketone of formula III:
where
PROT is a nitrogen protecting group, and
R 2 is:
chloro, bromo, or
—Si(R 21 ) 3 where each R 21 is independently C 1 -C 5 alkyl,
—N(R 23 ) (R 24 ) where R 23 and R 24 are the same or different and represent
C 1 -C 5 alkyl, or
where NR 23 R 24 represents piperidinyl, piperazinyl, or morpholinyl,
phenyl optionally substituted with 1, 2, or 3 of C 1 -C 2 alkyl, with the proviso that at least one of the R 21 groups is optionally substituted phenyl,
which process comprises:
(a) forming a mixture of an ester of formula II and a dihalogenated methane, R 2 CH 2 X 2 , where R 2 is as defined above and where X 2 is —Br or —I;
where
R 1 is selected from the group consisting of:
(I) C 1 -C 4 alkyl optionally substituted with one —Cl;
(II) —CH 2 —CH═CH 2 ,
(III) phenyl optionally substituted with one nitro, halogen, or cyano; and
(IV) benzyl optionally substituted on phenyl with nitro, halogen, or cyano; and
PROT is as defined above,
(b) adding a base to the mixture from (a);
(c) acidifying the mixture of (b)
42 . A process according to claim 41 where PROT is t-butoxycarbonyl or benzyloxycarbonyl.
43 . A process according to claim 41 where R 1 is C 1 -C 2 alkyl.
44 . A process according to claim 43 where R 1 is C 1 alkyl.
45 . A process according to claim 41 where R 2 is chloro or bromo.
46 . A process according to claim 45 where R 2 is chloro.
47 . A process according to claim 41 where CH 2 R 2 X 2 is present in an amount of from about 1 to about 1.5 equivalents based on the amount of ester II.
48 . A process according to claim 41 where X 2 is iodo.
49 . A process according to claim 41 where the strong base is LDA, (C 1 -C 8 alkyl)lithium, LiHMDS, NaHMDS or KHMDS.
50 . A process according to claim 49 where the strong base is LDA.
51 . A process according to claim 41 where the strong base is present in an amount of from about 2 to about 2.5 equivalents based on the amount of ester II.
52 . A process according to claim 41 where a second portion of base is added, where the second portion of base is (C 1 -C 4 )alkyl lithium, phenyl lithium, (C 1 -C 4 )alkyl-Grignard or phenyl-Grignard.
53 . A process according to claim 52 where the second base is phenyl lithium, n-butyl lithium, sec-butyllithium, tert-butyllithium, methyllithium, methyl magnesium bromide, methyl magnesium chloride, phenyl magnesium bromide or phenyl magnesium chloride.
54 . A process according to claim 53 where the second base is n-butyl lithium.
55 . A process according to claim 41 where amount of the second is from about 1 to about 1.5 equivalents based on the amount of the ester II.
56 . A process according to claim 41 where the acidifying is carried out using an acid having a PK a of less than about 10.
57 . A process according to claim 56 where the acid is selected from the group consisting of acetic, sulfuric, hydrochloric, citric, phosphoric, nitric, paratoluenesulfonic, and benzoic acids and mixtures thereof.
58 . A process according to claim 57 where the acid is hydrochloric acid or acetic acid.
59 . A process for according to claim 41 where the ketone (III) is tert-butyl (1S)-3-chloro-1-(3,5-difluorobenzyl)-2-oxopropylcarbarnate.
60 . A process for the preparation of a ketone of formula (III)
where PROT is a nitrogen protecting group, and
where R 2 is —Cl or —Br,
which process comprises:
(a) contacting an acid R 2 —CH 2 —COOH, where R 2 is as defined above, with a base;
(b) contacting the mixture of (a) with an ester of formula (II)
where R 1 is selected from the group consisting of:
(I) C 1 -C 4 alkyl optionally substituted with one —Cl;
(II) —CH 2 —CH═CH 2 ,
(III) phenyl optionally substituted with one:
(A) —NO 2 ,
(B) —F, —Cl, —Br, —I,
(C) —C≡N, and
(IV) —CH 2 —φ where the —φ ring is optionally substituted with
(A) —NO 2 ,
(B) —F, —Cl, —Br, —I,
(C) —C≡N and
where PROT is as defined above; and
(c) acidifying the mixture of (b).
61 . A process according to claim 60 where PROT is t-butoxycarbonyl or benzyloxycarbonyl.
62 . A process according to claim 60 where R 1 is C 1 -C 2 alkyl.
63 . A process according to claim 62 where R 1 is C 1 alkyl.
64 . A process according to claim 60 where R 2 is chloro or bromo.
65 . A process according to claim 64 where R 2 is chloro.
66 . A process according to claim 60 where the base is a strong base and is LDA, (C 1 -C 8 alkyl)lithium, LiHMDS, NaHMDS or KHMDS.
67 . A process according to claim 66 where the strong base is LDA.
68 . A process according to claim 60 where the strong base is present in an amount of from about 3 to about 3.5 equivalents based on the amount of ester II.
69 . A process according to claim 60 where the acidifying is carried out using an acid having a pK a of less than about 10.
70 . A process according to claim 69 where the acid is selected from the group consisting of acetic, sulfuric, hydrochloric, citric, phosphoric and benzoic acids and mixtures thereof.
71 . A process according to claim 70 where the acid is hydrochloric or acetic acid.
72 . A process for the preparation of a compound of formula (XI)
where X 1 is where X 1 is —Cl, —Br or imidazolyl;
where PROT is a nitrogen protecting group,
which process comprises
( 1 ) contacting a protected amino acid of formula (I)
where PROT is as defined above,
with thionyl chloride, SO 2 Cl 2 , phosphorous trichloride, oxalyl chloride, phosphorous tribromide, triphenyiphosphorous dibromide, oxalyl bromide, 1,2-phenylenetrichlorophosphate, 2,4,6-trichloro-1,3,5-triazine or CDI.
73 . A process according to claim 72 where PROT is t-butoxycarbonyl or benzyloxycarbonyl.
74 . A process according to claim 72 where X 1 is chloro.
75 . A process according to claim 72 where the compound of formula XI is contacted with thionyl chloride or oxalyl chloride.
76 . A process according to claim 72 where the process produces t-butyl-(1S)-2-chloro-1-[3,5-difluorobenzyl]-2-oxoethylcarbamate.
77 . A process for the preparation of ketone of formula (III)
where
R 2 is —Cl or —Br; and
PROT is a nitrogen protecting group,
which process comprises:
(1) contacting a compound of formula (XI)
where
X 1 is —Cl, —Br and imidazolyl; and
PROT is as defined above,
with LiCH 2 C 1 or LiCH 2 Br.
78 . A process according to claim 77 where PROT is t-butoxycarbonyl or benzyloxycarbonyl.
79 . A process according to claim 77 where X 1 is chloro.
80 . A process according to claim 77 where R 2 is chloro.
81 . A process according to claim 77 where the process produces tert-butyl (1S)-3-chloro-1-(3,5-difluorobenzyl)-2-oxopropylcarbamate.
82 . A process for the preparation of an ester of the formula (II)
where
R 1 is selected from the group consisting of:
(I) C 1 -C 4 alkyl optionally substituted with one —Cl;
(II) —CH 2 —CH═CH 2 ,
(III) phenyl optionally substituted with one:
(A) —NO 2 ,
(B) —F, —Cl, —Br, —I,
(C) —C≡N,
(IV) —CH 2 -φ where the -φ ring is optionally substituted with
(A) —NO 2 ,
(B) —F, —Cl, —Br, —I,
(C) —C≡N; and
PROT is a nitrogen protecting group,
which process comprises:
(b) treating a compound of formula XIV
where R 1 and PROT are as defined above; and
in a solvent with hydrogen in the presence of a hydrogenation catalyst at a pressure of from 1 atmosphere to about 100 psi.
83 . A process according to claim 82 where the PROT is t-butoxycarbonyl or benzyloxycarbonyl.
84 . A process according to claim 82 where R 1 is C 1 -C 2 alkyl.
85 . A process according to claim 84 where R 1 is C 1 alkyl.
86 . A process according to claim 82 where the solvent of step (a) is degassed.
87 . A process according to claim 82 where the reaction vessel is purged of oxygen after step (1) and before step (2).
88 . A process according to claim 69 where the hydrogenation catalyst is a compound of the formula [Rh (diene) L] + X − where Rh is rhodium; where diene is cyclootediene and nonbornadiene; where L is DIPMAP, MeDuPhos, EtiDuPhos, Binaphane, f-Binaphane, Me-KetalPhos, Me-f-KetalPhos, Et-f-KetalPhos, BINAP, DIOP, BPPFA, BPPM, CHIRAPHOS, PROPHOS, NORPHOS, CYCLOPHOS, BDPP, DEGPHOS, PNNP and where X is ClO 4 − , BF 4 − , CF 3 —SO 3 − , Cl − , Br − , PF 6 − and SbF 6 − .
89 . A process according to claim 88 where the hydrogenation catalyst is DIPMAP.
90 . A process according to claim 88 where the hydrogenation catalyst is EtDuPhos.
91 . A process according to claim 82 where the reaction temperature is from about 0° to about reflux.
92 . A process according to claim 91 where the reaction temperature is from about 0° to about 25°.
93 . A process according to claim 82 where the reaction pressure is from about 1 atmosphere to about 70 psig.
94 . A process according to claim 93 where the reaction pressure is from about 10 psig to about 40 psig.
95 . A process according to claim 82 where the ester (II) is obtained in greater than 90% enantiomeric purity.
96 . A process according to claim 95 where the ester (II) is obtained in greater than 95% enantiomeric purity.
97 . A process according to claim 82 where the ester (II) is methyl (2S)-2-{[(benzyloxy)carbonyl]amino}-3-(3,5-difluorophenyl)propanoate.
98 . A process for preparing an epoxide of formula V-R
comprising
(a) converting an ester of Formula II into a ketone of formula III
(b) reducing the ketone to the corresponding alcohol of formula IV; and
(c) treating the alcohol with a base to yield the epoxide.
99 . A process according to claim 98 further comprising esterifying an acid of formula (O) to generate the ester of formula II.
100 . A process for preparing a compound of formula (XX)
wherein
R 57 is H, C 1 -C 6 alkyl, or benzyl;
R 1 is —(CH 2 ) 1-2 —S(O) 0-2 —(C 1 -C 6 alkyl) , —CH 2 —CH 2 —S(O) 0-2 —(C 1 -C 6 alkyl), or
C 1 -C 6 alkyl optionally substituted with 1, 2, or 3 groups independently selected from halogen, —F, —Cl, —Br, —I, —OH, ═O, —SH, —C≡N, —CF 3 , —C 1 -C 3 alkoxy, amino, mono- or dialkylamino, —N(R)C(O)R′—, —OC(═O)—amino and —OC(═O) -mono- or dialkylamino, or
C 2 -C 6 alkenyl or C 2 -C 6 alkynyl, each of which is optionally substituted with 1, 2, or 3 groups independently selected from halogen, —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF 3 , C 1 -C 3 alkoxy, amino, and mono- or dialkylamino, or
aryl, heteroaryl, heterocyclyl, —C 1 -C 6 alkyl-aryl, —C 1 -C 6 alkyl-heteroaryl, or —C 1 -C 6 alkyl-heterocyclyl, where the ring portions of each are optionally substituted with 1, 2, 3, or 4 groups independently selected from halogen, —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —NR 7 R′ 7 , —C(═O)—(C 1 -C 4 ) alkyl, —SO 2 -amino, —SO 2 -mono or dialkylamino, —C(═O) -amino, —C(═O) -mono or dialkylamino, —SO 2 —(C 1 -C 4 ) alkyl, —CO 2 R, —N(R)COR′, or —N(R)SO 2 R′ or
—C 1 -C 6 alkoxy optionally substituted with 1, 2, or 3 groups which are independently a selected from halogen, or
C 3 -C 7 cycloalkyl optionally substituted with 1, 2, or 3 groups independently selected from halogen, —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF 3 , C 1 -C 3 alkoxy, amino, —C 1 -C 6 alkyl and mono- or dialkylamino, or
C 1 -C 10 alkyl optionally substituted with 1, 2, or 3 groups independently selected from halogen, —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF 3 , —C 1 -C 3 alkoxy, amino, mono- or dialkylamino and —C 1 -C 3 alkyl, or
C 2 -C 6 alkenyl or C 2 -C 6 alkynyl, each of which is optionally substituted with 1, 2, or 3 groups independently selected from halogen, —F, —Cl, —Br, —I, —OH, —SH, —C≡N, —CF 3 , C 1 -C 3 alkoxy, amino, —C 1 -C 6 alkyl and mono- or dialkylamino; and the heterocyclyl group is optionally further substituted with oxo;
R 7 and R 7 ′ are independently H or —C 1 -C 6 alkyl;
R 2 and R 3 are independently selected from the group consisting of H; C 1 -C 6 alkyl optionally substituted with one, two or three substituents independently selected from the group consisting of C 1 -C 3 alkyl, halogen, —OH, —SH, —C≡N, —CF 3 , C 1 -C 3 alkoxy, and —NR 30 R 31 ; —(CH 2 ) 0-4 -aryl; —(CH 2 ) 0-4 -heteroaryl; —(CH 2 ) 0-4 -heterocycle; C 2 -C 6 alkenyl optionally substituted with one, two or three substituents independently selected from the group consisting of —F, —Cl, —OH, —SH, —C≡N, —CF 3 , C 1 -C 3 alkoxy, and —NR 30 R 31 C 2 -C 6 alkynyl optionally substituted with one, two or three substituents independently selected from the group consisting of —F, —Cl, —OH, —SH, —C≡N, —CF 3 , C 1 -C 3 alkoxy, and —NR 30 R 31 and —(CH 2 ) 0-4 -C 3 -C 7 cycloalkyl, wherein the cycloalkyl group is optionally substituted with one, two or three substituents independently selected from the group consisting of —F, —Cl, —OH, —SH, —C≡N, —CF 3 , C 1 -C 3 alkoxy, and —NR 30 R 31 ;
or
R 2 , R 3 and the carbon to which they are attached form a carbocycle of three, four, five, six, or seven carbon atoms, wherein 1, 2, or 3 carbon atoms are optionally replaced by a heteroatom independently selected from the group consisting of —O—, —S—, —SO 2 —, and —NR 22 —; wherein
R 30 and R 31 at each occurrence are independently H, or C 1 -C 6 alkyl;
R 22 is selected from the group consisting of —H, —C 1 -C 6 alkyl, hydroxy C 1 -C 6 alkyl, amino C 1 -C 6 alkyl; halo C 1 -C 6 alkyl; —C 3 -C 7 cycloalkyl, —(C 1 -C 2 alkyl)—(C 3 -C 7 cycloalkyl), —(C 1 -C 6 alkyl)—O—(C 1 -C 3 alkyl), —C 2 -C 6 alkenyl, —C 2 -C 6 alkynyl, —C 1 -C 6 alkyl chain with one double bond and one triple bond, aryl, heteroaryl, and heterocycloalkyl;
R c is selected from the group consisting of C 1 -C 10 alkyl optionally substituted with 1, 2, or 3 groups independently selected from the group consisting of R 205 , —OC═O NR 235 R 240 , —S (═ 0 ) 0-2 R 23 , —NR 235 C═ 0 NR 235 R 240 , —C═O NR 235 R 240 , and —S (═O) 2 NR 235 R 240 ; —(CH 2 ) 0-3 (C 3 -C 8 ) cycloalkyl wherein the cycloalkyl is optionally substituted with 1, 2, or 3 groups independently selected from the group consisting of R 205 , —CO 2 H, and —CO 2 —(C 1 -C 4 alkyl); —(CR 245 R 250 ) 0-4 -aryl; —(CR 245 R 250 ) 0-4 -heteroaryl, —(CR 245 R 250 ) 0-4 -heterocycloalkyl; —(CR 245 R 250 ) 0-4 -aryl-heteroaryl; —(CR 245 R 250 ) 0-4 -aryl-heterocycloalkyl; —(CR 245 R 250 ) 0-4 -aryl-aryl; —(CR 245 R 250 ) 0-4 -heteroary 1 -ary 1 ; —(CR 245 R 250 ) 0-4 -heteroaryl-heterocycloalkyl; —(CR 245 R 250 ) 0-4 -heteroaryl-heteroaryl; —(CR 245 R 250 ) 0-4 -heterocycloalkyl-heteroaryl; —(CR 245 R 250 ) 0-4 -heterocycloalkyl-heterocycloalkyl; —(CR 245 R 250 ) 0-4 -heterocycloalkyl-aryl; —[C(R 255 ) (R 260 )] 1-3 —CO—N—(R 255 ) 2 ; —CH(aryl) 2 ; —CH(heteroaryl) 2 ; —CH(heterocycloalkyl) 2 ; —CH(aryl) (heteroaryl); cyclopentyl, cyclohexyl, or cycloheptyl ring fused to aryl, heteroaryl, or heterocycloalkyl wherein one carbon of the cyclopentyl, cyclohexyl, or cycloheptyl is optionally replaced with NH, NR 215 , O, or S(═O) 0-2 , and wherein the cyclopentyl, cyclohexyl, or -cycloheptyl group can be optionally substituted with 1 or 2 groups that are independently R 205 or ═O; —CO—NR 235 R 240 ; or —SO 2 —(C 1 -C 4 alkyl); C 2 -C 10 alkenyl optionally substituted with 1, 2, or 3 R 205 groups; C 2 -C 10 alkynyl optionally substituted with 1, 2, or 3 R 205 groups; —(CH 2 ) 0-1 —CH ((CH 2 ) 0-6 -OH)—(CH 2 ) 0-1 -aryl; —(CH 2 ) 0-1 —CHR c-6 —(CH 2 ) 0-1 -heteroaryl; —CH(-aryl or -heteroaryl) —CO—O(C 1 -C 4 alkyl); —CH(—CH 2 —OH)—CH(OH)-phenyl-NO 2 , (C 1 -C 6 alkyl)—O—(C 1 -C 6 alkyl)—OH, —CH 2 —NH—CH 2 —CH(—O—CH 2 —CH 3 ) 2 , —H, and —(CH 2 ) 0-6 -C(═NR 235 ) (NR 235 R 240 ); wherein
each aryl is optionally substituted with 1, 2, or 3 R 200 ;
each heteroaryl is optionally substituted with 1, 2, 3, or 4 R 200 ;
each heterocycloalkyl is optionally substituted with 1, 2, 3, or 4 R 210 ;
R 200 at each occurrence is independently selected from the group consisting of C 1 -C 6 alkyl optionally substituted with 1, 2, or 3 R 205 groups; OH; —NO 2 ; halogen; —CO 2 H; C≡N; —(CH 2 ) 0-4 —CO—NR 220 R 225 ; —(CH 2 ) 0-4 —CO—(C 1 -C 12 alkyl); —(CH 2 ) 0-4 —CO—(C 2 -C 12 alkenyl); —(CH 2 ) 0-4 —CO—(C 2 -C 12 alkynyl); —(CH 2 ) 0-4 —CO—(C 3 -C 7 cycloalkyl); —(CH 2 ) 0-4 —CO—aryl; —(CH 2 ) 0.4 —CO—heteroaryl; —(CH 2 ) 0-4 —CO—heterocycloalkyl; —(CH 2 ) 0-4 —CO—O—R 215 ; —(CH 2 ) 0-4 —SO 2 —NR 220 R 225 ; —(CH 2 ) 0-4 —SO—(C 1 -C 8 alkyl) ; —(CH 2 ) 0-4 —SO 2 (C 1 -C 12 alkyl); —(CH 2 ) 0-4 —SO 2 —(C 3 -C 7 cycloalkyl); —(CH 2 ) 0-4 —N(H or R 215 ) —CO—O—R 215 ; —(CH 2 ) 0-4 —N(H or R 215 ) —CO—N (R 215 ) 2 ; —(CH 2 ) 0-4 —N—CS—N (R 215 ) 2 ; —(CH 2 ) 0-4 13 N (—H or R 215 ) —CO—R 220 ; —(CH 2 ) 0-4 NR 220 R 225 ; —(CH 2 ) 0-4 —O—C 0 —(C 1 -C 6 alkyl) ; —(CH 2 ) 0-4 —O—P (O)—(OR 240 ) —(CH 2 ) 0-4 —O—CO—N (R 215 ) 2 ; —(CH 2 ) 0-4 —O—CS—N (R 215 ) 2 ; —(CH 2 ) 0-4 —O—(R 215 ) 2 —(CH 2 ) 0-4 —O—(R 215 ) 2 -COOH; —(CH 2 ) 0-4 —S—(R 215 ) 2 ; —(CH 2 ) 0-4 —O—(C 1 -C 6 alkyl optionally substituted with 1, 2, 3, or 5 -F); C 3 -C 7 cycloalkyl; C 2 -C 6 alkenyl optionally substituted with 1 or 2 R 205 groups; C 2 -C 6 alkynyl optionally substituted with 1 or 2 R 205 groups; —(CH 2 ) 0-4 —N(H or R 215 ) —SO 2 -R 220 ; and —(CH 2 ) 0-4 —C 3 -C 7 cycloalkyl;
wherein each aryl group at each occurrence is optionally substituted with 1, 2, or 3 groups that are independently R 205 , R 210 or C 1 -C 6 alkyl substituted with 1, 2, or 3 groups that are independently R 205 or R 210 ;
wherein each heterocycloalkyl group at each occurrence is optionally substituted with 1, 2, or 3 groups that are independently R 210 ;
wherein each heteroaryl group at each occurrence is optionally substituted with 1, 2, or 3 groups that are independently R 205 , R 210 , or C 1 -C 6 alkyl substituted with 1, 2, or 3 groups that are independently R 205 or R 210 ;
R 205 at each occurrence is independently selected from the group consisting of C 1 -C 6 alkyl, halogen, —OH, —O—phenyl, —SH, —C≡N, —CF 3 , C 1 -C 6 alkoxy, NH 2 , NH(C 1 -C 6 alkyl), and N—(C 1 -C 6 alkyl) (C 1 -C 6 alkyl);
R 210 at each occurrence is independently selected from the group consisting of C 1 -C 6 alkyl optionally substituted with 1, 2, or 3 R 205 groups; C 2 -C 6 alkenyl optionally substituted with 1, 2, or 3 R 205 groups; C 2 -C 6 alkynyl optionally substituted with 1, 2, or 3 R 205 groups; halogen; C 1 -C 6 alkoxy; C 1 -C 6 haloalkoxy; —NR 220 R 225 ; OH; C═N; C 3 -C 7 cycloalkyl optionally substituted with 1, 2, or 3 R 205 groups; —CO—(C 1 -C 4 alkyl) ; SO 2 NR 235 R 240 ; —CO—NR 235 R 240 ; —SO 2 —(C 1 -C 4 alkyl); and ═O; wherein
R 215 at each occurrence is independently selected from the group consisting of C 1 -C 6 alkyl, —(CH 2 ) 0-2 —(aryl), C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 7 , cycloalkyl, and —(CH 2 ) 0-2 —(heteroaryl), —(CH 2 ) 0-2 —(heterocycloalkyl); wherein the aryl group at each occurrence is optionally substituted with 1, 2, or 3 groups that are independently R 205 or R 210 ; wherein the heterocycloalkyl group at each occurrence is optionally substituted with 1, 2, or 3 R 210 ; wherein each heteroaryl group at each occurrence is optionally substituted with 1, 2, or 3 R 210 ;
R 220 and R 225 at each occurrence are independently selected from the group consisting of —H, —C 1 -C 6 alkyl, hydroxy C 1 -C 6 alkyl, amino C 1 -C 6 alkyl; halo C 1 -C 5 alkyl; —C 3 -C 7 cycloalkyl, —C 1 -C 2 alkyl)—(C 3 -C 7 cycloalkyl), —(C 1 -C 6 alkyl)—O—(C 1 -C 3 alkyl), —C 2 -C 6 alkenyl, —C 2 -C 6 alkynyl, —C 1 -C 6 alkyl chain with one double bond and one triple bond, -aryl, -heteroaryl, and -heterocycloalkyl;
wherein the aryl group at each occurrence is optionally substituted with 1, 2, or 3 groups that are independently R 205 or R 210 ;
wherein the heterocycloalkyl group at each occurrence is optionally substituted with 1, 2, or 3 R 210 ;
wherein each heteroaryl group at each occurrence is optionally substituted with 1, 2, or 3 R 235 and R 240 at each occurrence are independently H, or C 1 -C 6 alkyl;
R 245 and R 250 at each occurrence are independently selected from the group consisting of H, C 1 -C 4 alkyl, C 1 -C 4 hydroxyalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, —(CH 2 ) 0-4 —C 3 -C 7 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, and phenyl; or
R 245 and R 250 are taken together with the carbon to which they are attached to form a carbocycle of 3, 4, 5, 6, or 7 carbon atoms, optionally where one carbon atom is replaced by a heteroatom selected from the group consisting of —O—, —S—, —SO 2 —, and —NR 220 —;
R 255 and R 260 at each occurrence are independently selected from the group consisting of H; C 1 -C 6 alkyl optionally substituted with 1, 2, or 3 R 205 groups; C 2 -C 6 alkenyl optionally substituted with 1, 2, or 3 R 205 groups; C 2 -C 6 alkynyl optionally substituted with 1, 2, or 3 R 205 groups; —(CH 2 ) 1-2 —S(O) 0-2 —(C 1 -C 6 alkyl); —(CH 2 ) 0-4 —C 3 -C 7 cycloalkyl optionally substituted with 1, 2, or 3 R 205 groups; —(C 1 -C 4 alkyl)-aryl; —(C 1 -C 4 alkyl) -heteroaryl; —(C 1 -C 4 alkyl) -heterocycloalkyl; -aryl; -heteroaryl; -heterocycloalkyl; (CH 2 ) 1-4 -R 265 —(CH 2 ) 0-4 -aryl; —(CH 2 ) 1-4 -R 265 —(CH 2 ) 0-4 -heteroaryl; and; —(CH 2 ) 1-4 -R 265 —(CH 2 ) 0-4 -heterocycloalkyl; wherein R 265 at each occurrence is independently —O—, —S— or —N(C 1 -C 6 alkyl)—;
each aryl or phenyl is optionally substituted with 1, 2, or 3 groups that are independently R 205 , R 210 , or C 1 -C 6 alkyl substituted with 1, 2, or 3 groups that are independently R 205 or R 210 ;
each heteroaryl is optionally substituted with 1, 2, 3, or 4 R 200 ,
each heterocycloalkyl is optionally substituted with 1, 2, 3, or 4 R 210 ;
R N is —C(═O)—(CRR′) 0-6 R 100 , R′ 100 , —SO 2 R′ 100 , —(CRR′) 1-6 R′ 100 , —C(═O)—(CRR′)—O—R′ 100 , —C(═O)—(CRR′)—S—R′ 100 or —C(═O)—(CRR′)—NR 100 —R′ 100 ;
R 100 and R′ 100 are independently aryl, heteroaryl, -aryl-W-aryl, -aryl-W-heteroaryl, -aryl-W-heterocyclyl, -heteroaryl-W-aryl, -heteroaryl-W-heteroaryl, -heteroaryl-W-heterocyclyl, -heterocyclyl-W-aryl, -heterocyclyl-W-heteroaryl, -heterocyclyl-W-heterocyclyl, —C(═O) —CH[(CH 2 ) 0-2 —O—R 7 ]—(CH 2 ) 0 . 2 -aryl, —C (═O) —CH[(CH 2 ) 0-2 —O—R 7 ]—(CH 2 ) 0-2 -heterocyclyl, or —C(═O)—CH[(CH 2 ) 0-2 —O—R 7 ]—(CH 2 ) 0-2 -heteroaryl, where the ring portions of each are optionally substituted with 1, 2, or 3 groups independently selected from
—OR, —NO 2 , halogen, 13 C≡N, —SR, —SO 2 R 145 , —C(═O)R, —OCF 3 , —CF 3 , —O—P(═O) (OR) (OR′), —N(R) (COR′) , —N(R) (SO 2 R 145 ) —(CH 2 ) 0-4 —CO—NR 105 R′ 105 , —(CH 2 ) 0-4 —O—(CH 2 ) 0-4 —CONRR′, —(CH 2 ) 0-4 —CO—(C 1 -C 12 alkyl), —(CH 2 ) 0-4 —CO—(C 2 -C 12 alkenyl), —(CH 2 ) 0-4 —CO—(C 2 -C 12 alkynyl), —(CH 2 ) 0-4 —CO—(C 3 -C 7 cycloalkyl) , —(CH 2 ) 0-4 -R 110 , —(CH 2 ) 0-4 -R 120 , —(CH 2 ) 0-4 —R 130 , —(CH 2 ) 0-4 —CO—R 110 , —(CH 2 ) 0-4 —CO—R 120 , —(CH 2 ) 0-4 —CO—R 130 , —(CH 2 ) 0-4 —CO—R 140 , —(CH 2 ) 0-4 —CO—R 150 , —(CH 2 ) 0-4 —SO 2 —NR 105 R′, —(CH 2 ) 0-4 —SO—(C 1 -C 8 alkyl), —(CH 2 ) 0-4 —SO 2 —(C 1 -C 12 alkyl), —(CH 2 ) 0-4 —SO 2 —(C 3 -C 7 cycloalkyl), —(CH 2 ) 0-4 —N(H or R 150 )—CO—O—R 150 , —(CH 2 ) 0-4 —N(H or R 150 )—CO—N (R 150 ) 2 , —(CH 2 ) 0-4 —N(H or R 150 )—CS—N (R 150 ) 2 , —(CH 2 ) 0-4 —N (—H or R 150 )—CO—R 105 , —(CH 2 ) 0-4 —NR 105 R′ 105 , —(CH 2 ) 0-4 —R 140 , —(CH 2 ) 0-4 —O—CO—(C 1 -C 6 alkyl), —(CH 2 ) 0-4 —O—P (O)—(O—R 110 ) 2 , —(CH 2 ) 0-4 —O—CO—N (R 150 ) 2 , —(CH 2 ) 0-4 —O—CS—N (R 150 ) 2 , —(CH 2 ) 0-4 —O—(R 150 ) , —(CH 2 ) 0-4 —O—(R 155 )—COOH, —(CH 2 ) 0-4 —S—(R 150 ), C 3 -C 7 cycloalkyl, —(CH 2 ) 0-4 —N(—H or R 150 )—SO 2 —R 7 , or —(CH 2 ) 0-4 —C 3 -C 7 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, or
R 100 is C 1 -C 10 alkyl optionally substituted with 1, 2, or 3 R 115 groups, wherein
R 115 at each occurrence is independently halogen, —OH, —CO 2 R, —C 1 -C 6 thioalkoxy, —CO 2 -phenyl, —NR 105 R′ 7 , —SO 2 —(C 1 -C 8 alkyl) , —C (═ 0 ) R 180 , R 180 , —CONR 105 R′ 105 , —SO 2 NR 105 R′ 105 , —NH—Ca—(C 1 -C 6 alkyl), —NH—C(═O) —OH, —NH—C(═O)—OR, —NH—C(═O)—O—phenyl, —O—C(═O)—(C 1 -C 6 alkyl), —O—C(═O)-amino, —O—C(═O)-mono- or dialkylamino, —O—C(═O)-phenyl, —O—(C 1 -C 6 alkyl)—CO 2 H, —NH—SO 2 —(C 1 -C 5 alkyl), C 1 -C 6 alkoxy or C 1 -C 6 haloalkoxy; or
R 100 is —(C 1 -C 5 alkyl)—O—(C 1 -C 6 alkyl) or —(C 1 -C 6 alkyl)—S—(C 1 -C 6 alkyl), each of which is optionally substituted with 1, 2, or 3 R 115 groups, or
R 100 is —(C 3 -C 8 cycloalkyl) optionally substituted with 1, 2,or 3 R 115 groups;
R and R′ independently are hydrogen; C 1 -C 6 alkyl optionally substituted with 1, 2, or 3 groups that are independently F, Cl, Br, or I; or —(C 1 -C 6 )—R 110 ;
W is —(CH 2 ) 0-4 , —O—, —S(O) 0-2 , —N (R 135 )—, or —C (O)—;
R 7 and R 7 ′ are independently selected from the group consisting of H, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, aryl, heteroaryl, and heterocyclyl,
R 105 and R′ 105 are the same or different and represent —H, —R 110 , —R 120 , —C 3 -C 7 cycloalkyl, —(C 1 -C 2 alkyl)—(C 3 -C 7 cycloalkyl), —(C 1 -C 6 alkyl)—O—(C 1 -C 3 alkyl), —C 2 -C 6 alkenyl, —C 2 -C 6 alkynyl, or —C 1 -C 6 alkyl chain with one double bond and one triple bond, or
—C 1 -C 5 alkyl optionally substituted with —OH or —NH 2 ; or,
—C 1 -C 6 alkyl optionally substituted with 1, 2, or 3 groups independently selected from halogen;
R 135 is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 7 cycloalkyl, —(CH 2 ) 0-2 —(aryl), —(CH 2 ) 0-2 —(heteroaryl), or —(CH 2 ) 0-2 —(heterocyclyl),
R 140 is heterocyclyl optionally substituted with 1, 2, 3, or 4 groups independently selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halogen, hydroxy, cyano, nitro, amino, mono(C 1 -C 6 )alkylamino, di(C 1 -C 6 )alkylamino, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, amino(C 1 -C 6 )alkyl, mono(C 1 -C 6 )alkylamino(C 1 -C 6 )alkyl, di(C 1 -C 6 )alkylamino(C 1 -C 6 )alkyl, and ═O;
R 145 is C 1 -C 6 alkyl or CF 3 ;
R 150 is hydrogen, C 3 -C 7 cycloalkyl, —(C 1 -C 2 alkyl)—(C 3 -C 7 cycloalkyl), C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkyl with one double bond and one triple bond, —R 110 , —R 120 , or C 1 -C 6 alkyl optionally substituted with 1, 2, 3, or 4 groups independently selected from —OH, —NH 2 , C 1 -C 3 alkoxy, R 110 , and halogen;
R 155 is C 3 -C 7 cycloalkyl, —(C 1 -C 2 alkyl)—(C 3 -C 7 cycloalkyl), C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkyl with one double bond and one triple bond, —R 110 , —R 120 , or
C 1 -C 6 alkyl optionally substituted with 1, 2, 3, or 4 groups independently selected from —OH, —NH 2 , C 1 -C 3 alkoxy, and halogen;
R 180 is selected from morpholinyl, thiomorpholinyl, piperazinyl, piperidinyl, homomorpholinyl, homothiomorpholinyl, homothiomorpholinyl S-oxide, homothiomorpholinyl S,S-dioxide, pyrrolinyl and pyrrolidinyl, each of which is optionally substituted with 1, 2, 3, or 4 groups independently selected from C 1 -C 6 alkyl C 1 -C 6 alkoxy, halogen, hydroxy, cyano, nitro, amino, mono (C 1 -C 6 )alkylamino, di(C 1 -C 6 )alkylamino, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, amino(C 1 -C 6 )alkyl, mono(C 1 -C 6 )alkylamino(C 1 -C 6 )alkyl, di(C 1 -C 6 )alkylamino(C 1 -C 6 )alkyl, and ═O; R 110 is aryl optionally substituted with 1 or 2 R 125 groups, wherein,
R 125 at each occurrence is independently halogen, amino, mono- or dialkylamino, —OH, —C≡N, —SO 2 —NH 2 , —SO 2 —NH—C 1 -C 6 alkyl, —SO 2 —N(C 1 -C 6 alkyl) 2 , —SO 2 —(C 1 -C 4 alkyl), —CO—NH 2 , —CO—NH—C 1 -C 6 alkyl, or —CO—N(C 1 -C 6 alkyl) 2 ; or
C 1 -C 6 alkyl, C 2 -C 6 alkenyl or C 2 -C 6 alkynyl, each of which is optionally substituted with 1, 2, or 3 groups that are independently selected from C 1 -C 3 alkyl, halogen, —OH, —SH, —C≡N, —CF 3 , C 1 -C 3 alkoxy, amino, and mono- and dialkylamino; or
C 1 -C 6 alkoxy optionally substituted with one, two or three of halogen;
R 120 is heteroaryl, which is optionally substituted with 1 or 2 R 125 groups; and
R 130 is heterocyclyl optionally substituted with 1 or 2 R 125 groups;
comprising
(a) reducing a ketone of formula III to generate an alcohol of formula IV; and
(b) treating the alcohol of formula IV with a base to generate an epoxide.
101 . A process according to claim 100 , further comprising contacting the epoxide with an amine of formula R c NH(R 57 ) to yield a protected amine of formula VII-1.
102 . A process according to claim 101 , further comprising forming a deprotected amine of formula VIII-1 and forming an amide using the amine of formula VIII-1 and a compound of the R N COZ, wherein Z is OH, Cl, or imidazolyl.
103 . An amino alcohol of the formula:
where
R is phenyl optionally substituted with 1, 2, 3, or 4 groups independently selected from:
(A) C 1 -C 6 alkyl optionally substituted with one, two or three substituents independently selected from C 1 -C 3 alkyl, halogen, hydroxy, thio, —NR 10 R 11 where R 10 and R 11 are independently hydrogen or C 1 -C 6 alkyl, cyano, trifluoromethyl, and C 1 -C 3 alkoxy,
(B) C 2 -C 6 alkenyl or C 2 -C 6 alkynyl,
(C) halogen, hydroxy, cyano, C 1 -C 6 alkoxy optionally substituted with 1, 2, or 3 fluoro,
(D) —NR 12 R 13 where at each occurrence R 12 and R 13 are the same or different and represent:
(a) —H,
(b) —C 1 -C 8 alkyl optionally substituted with one of:
(i) —OH,
(ii) —NH 2 ,
(iii) phenyl,
(c) —C 1 -C 8 alkyl optionally substituted with 1, 2, or 3 independently selected halogens,
(d) —C 3 -C 8 cycloalkyl, —(C 1 -C 2 alkyl)-(C 3 -C 8 cycloalkyl), —(C 1 -C 6 alkyl)—O—(C 1 -C 3 alkyl), —C 2 -C 6 alkenyl, —C 2 -C 6 alkynyl; and
(E) C 3 -C 7 cycloalkyl, —C(O) (C 1 -C 4 alkyl), —SO 2 NR 10 R 11 , —C(O)NR 10 R 11 , or —SO 2 (C 1 -C 4 alkyl); and
R 2 is:
chloro, bromo, or
—Si(R 21 ) 3 where each R 21 is independently C 1 -C 5 alkyl,
—N(R 23 )(R 24 ) where R 23 and R 24 are the same or different and represent
C 1 -C 5 alkyl,
or where NR 23 R 24 represents piperidinyl, piperazinyl, or morpholinyl,
phenyl optionally substituted with 1, 2, or 3 of C 1 -C 2 alkyl, with the proviso that at least one of the R 21 groups is optionally substituted phenyl.
104 . A compound of the formula
where
R is phenyl optionally substituted with 1, 2, 3, or 4 groups independently selected from:
(A) C 1 -C 6 alkyl optionally substituted with one, two or three substituents independently selected from C 1 -C 3 alkyl, halogen, hydroxy, thio, —NR 10 R 11 where R 10 and R 11 are independently hydrogen or C 1 -C 6 alkyl, cyano, trifluoromethyl, and C 1 -C 3 alkoxy,
(B) C 2 -C 5 alkenyl or C 2 -C 6 alkynyl,
(C) halogen, hydroxy, cyano, C 1 -C 6 alkoxy optionally substituted with 1, 2, or 3 fluoro,
(D) —NR 12 R 13 where at each occurrence R 12 and R 13 are the same or different and represent:
(a) —H,
(b) —C 1 -C 8 alkyl optionally substituted with one of:
(i) —OH,
(ii) —NH 2 ,
(iii) phenyl,
(c) —C 1 -C 8 alkyl optionally substituted with 1, 2, or 3 independently selected halogens,
(d) —C 3 -C 8 cycloalkyl, —(C 1 -C 2 alkyl)-(C 3 -C 8 cycloalkyl), —(C 1 -C 6 alkyl)—O—(C 1 -C 3 alkyl), —C 2 -C 6 alkenyl, —C 2 -C 6 alkynyl; and
(E) C 3 -C 7 cycloalkyl, —C(O) (C 1 -C 4 alkyl) , —SO 2 NR 10 R 11 , —C(O)NR 10 R 11 , or —SO 2 (C 1 -C 4 alkyl).
105 . A compound of the formula
where
X 1 is chloro, bromo, or imidazolyl, or
X 1 is —CH 2 —R 2 , wherein
R 2 is chloro, bromo, or
—Si(R 21 ) 3 where each R 21 is independently C 1 -C 5 alkyl,
—N(R 23 )(R 24 ) where R 23 and R 24 are the same or different and represent
C 1 -C 5 alkyl,
or where NR 23 R 24 represents piperidinyl, piperazinyl, or morpholinyl,
phenyl optionally substituted with 1, 2, or 3 of C 1 -C 2 alkyl, with the proviso that at least one of the R 21 groups is optionally substituted phenyl;
R is phenyl optionally substituted with 1, 2, 3, or 4 groups independently selected from:
(A) C 1 -C 6 alkyl optionally substituted with one, two or three substituents independently selected from C 1 -C 3 alkyl, halogen, hydroxy, thio, —NR 10 R 11 where R 10 and R 11 are independently hydrogen or C 1 -C 6 alkyl, cyano, trifluoromethyl, and C 1 -C 3 alkoxy,
(B) C 2 -C 6 alkenyl or C 2 -C 6 alkynyl,
(C) halogen, hydroxy, cyano, C 1 -C 6 alkoxy optionally substituted with 1, 2, or 3 fluoro,
(D) —NR 12 R 13 where at each occurrence R 12 and R 13 are the same or different and represent:
(a) —H,
(b) —C 1 -C 8 alkyl optionally substituted with one of:
(i) —OH,
(ii) —NH 2 ,
(iii) phenyl,
(c) —C 1 -C 8 alkyl optionally substituted with 1, 2, or 3 independently selected halogens,
(d) —C 3 -C 8 cycloalkyl, —(C 1 -C 2 alkyl)-(C 3 -C 8 cycloalkyl), —(C 1 -C 6 alkyl)-O—(C 1 -C 3 alkyl), —C 2 -C 6 alkenyl, —C 2 -C 6 alkynyl; and
(E) C 3 -C 7 cycloalkyl, —C(O) (C 1 -C 4 alkyl), —SO 2 NR 10 R 11 , —C(O)NR 10 R 11 , or —SO 2 (C 1 -C 4 alkyl); and
PROT is a nitrogen protecting group.
106 . A compound of the formula
wherein
R 1 is selected from:
(I) C 1 -C 6 alkyl optionally substituted with one halogen;
(II) —CH 2 —CH═CH 2 ;
(III) phenyl optionally substituted with one nitro, halogen, or cyano; and
(IV) benzyl optionally substituted on phenyl with nitro, halogen, or cyano
R is phenyl optionally substituted with 1, 2, 3, or 4 groups independently selected from:
(A) C 1 -C 6 alkyl optionally substituted with one, two or three substituents independently selected from C 1 -C 3 alkyl, halogen, hydroxy, thio, —NR 10 R 11 where R 10 and R 11 are independently hydrogen or C 1 -C 6 alkyl, cyano, trifluoromethyl, and C 1 -C 3 alkoxy,
(B) C 2 -C 6 alkenyl or C 2 -C 6 alkynyl,
(C) halogen, hydroxy, cyano, C 1 -C 6 alkoxy optionally substituted with 1, 2, or 3 fluoro,
(D) —NR 12 R 13 where at each occurrence R 12 and R 13 are the same or different and represent:
(a) —H,
(b) —C 1 -C 3 alkyl optionally substituted with one of:
(i) —OH,
(ii) —NH 2 ,
(iii) phenyl,
(c) —C 1 -C 8 alkyl optionally substituted with 1, 2, or 3 independently selected halogens,
(d) —C 3 -C 8 cycloalkyl, —(C 1 -C 2 alkyl)-(C 3 -C 8 cycloalkyl), —(C 1 -C 6 alkyl)-O—(C 1 -C 3 alkyl), —C 2 -C 6 alkenyl, —C 2 -C 6 alkynyl; and
(E) C 3 -C 7 cycloalkyl, —C(O)(C 1 -C 4 alkyl), —SO 2 NR 10 R 11 , —C(O)NR 10 R 11 , or —SO 2 (C 1 -C 4 alkyl); and
PROT is a nitrogen protecting group.
107 . A process for preparing compounds of the formula
wherein
R 1 is selected from:
(I) C 1 -C 6 alkyl optionally substituted with one halogen;
(II) —CH 2 —CH═CH 2 ;
(III) phenyl optionally substituted with one nitro, halogen, or cyano; and
(IV) benzyl optionally substituted on phenyl with nitro, halogen, or cyano;
the process comprises
(1) esterifying a protected amino acid of the formula
wherein
R is phenyl optionally substituted with 1, 2, 3, or 4 groups independently selected from:
(A) C 1 -C 6 alkyl optionally substituted with one, two or three substituents independently selected from C 1 -C 3 alkyl, halogen, hydroxy, thio, —NR 10 R 11 where R 10 and R 11 are independently hydrogen or C 1 -C 6 alkyl, cyano, trifluoromethyl, and C 1 -C 3 alkoxy,
(B) C 2 -C 6 alkenyl or C 2 -C 6 alkynyl,
(C) halogen, hydroxy, cyano, C 1 -C 6 alkoxy optionally substituted with 1, 2, or 3 fluoro,
(D) —NR 12 R 13 where at each occurrence R 12 and R 13 are the same or different and represent:
(a) —H,
(b) —C 1 -C 8 alkyl optionally substituted with one of:
(i) —OH,
(ii) —NH 2 ,
(iii) phenyl,
(c) —C 1 -C 8 alkyl optionally substituted with 1, 2, or 3 independently selected halogens,
(d) —C 3 -C 8 cycloalkyl, —(C 1 -C 2 alkyl)-(C 3 -C 8 cycloalkyl), —(C 1 -C 6 alkyl)—O—(C 1 -C 3 alkyl), —C 2 -C 6 alkenyl, —C 2 -C 6 alkynyl; and
(E) C 3 -C 7 cycloalkyl, —C(O)(C 1 -C 4 alkyl), —SO 2 NR 10 R 11 , —C(O)NR 10 R 11 , or —SO 2 (C 1 -C 4 alkyl); and
PROT is a nitrogen protecting group;
with an alkylating agent in the presence of a base.
108 . A process for preparing compounds of the formula:
where R 1 is an optionally substituted phenyl;
R is phenyl optionally substituted with 1, 2, 3, or 4 groups independently selected from:
(A) C 1 -C 6 alkyl optionally substituted with one, two or three substituents independently selected from C 1 -C 3 alkyl, halogen, hydroxy, thio, —NR 10 R 11 where R 10 and R 11 are independently hydrogen or C 1 -C 6 alkyl, cyano, trifluoromethyl, and C 1 -C 3 alkoxy,
(B) C 2 -C 6 alkenyl or C 2 -C 6 alkynyl,
(C) halogen, hydroxy, cyano, C 1 -C 6 alkoxy optionally substituted with 1, 2, or 3 fluoro,
(D) —NR 12 R 13 where at each occurrence R 12 and R 13 are the same or different and represent:
(a) —H,
(b) —C 1 -C 8 alkyl optionally substituted with one of:
(i) —OH,
(ii) —NH 2 ,
(iii) phenyl,
(c) —C 1 -C 8 alkyl optionally substituted with 1, 2, or 3 independently selected halogens,
(d) —C 3 -C 8 cycloalkyl, —(C 1 -C 2 alkyl)—(C 3 -C 8 cycloalkyl), —(C 1 -C 6 alkyl)-O-(C 1 -C 3 alkyl), —C 2 -C 6 alkenyl, —C 2 -C 6 alkynyl; and
(E) C 3 -C 7 cycloalkyl, —C(O) (C 1 -C 4 alkyl), —SO 2 NR 10 R 11 , —C(O)NR 10 R 11 , or —SO 2 (C 1 -C 4 alkyl); and
PROT is a nitrogen protecting group;
the process comprising:
(a) forming a mixture of an activating agent and a protected amino acid of the formula
(b) contacting the mixture of (a) with a phenol optionally substituted on the phenyl ring with nitro, halogen, or cyano.
109 . A method for preparing a compound of the formula
where R 1 is selected from:
(I) C 1 -C 6 alkyl optionally substituted with one halogen;
(II) —CH 2 —CH—CH 2
(III) phenyl optionally substituted with one nitro, halogen, or cyano; and
(IV) benzyl optionally substituted on phenyl with nitro, halogen, or cyano;
R is phenyl optionally substituted with 1, 2, 3, or 4 groups independently selected from:
(A) C 1 -C 6 alkyl optionally substituted with one, two or three substituents independently selected from C 1 -C 3 alkyl, halogen, hydroxy, thio, —NR 10 R 11 where R 10 and R 11 are independently hydrogen or C 1 -C 6 alkyl, cyano, trifluoromethyl, and C 1 -C 3 alkoxy,
(B) C 2 -C 6 alkenyl or C 2 -C 6 alkynyl,
(C) halogen, hydroxy, cyano, C 1 -C 6 alkoxy optionally substituted with 1, 2, or 3 fluoro,
(D) —NR 12 R 13 where at each occurrence R 12 and R 13 are the same or different and represent:
(a) —H,
(b) —C 1 -C 8 alkyl optionally substituted with one of:
(i) —OH,
(ii) —NH 2 ,
(iii) phenyl,
(c) —C 1 -C 8 alkyl optionally substituted with 1, 2, or 3 independently selected halogens,
(d) —C 3 -C 8 cycloalkyl, —(C 1 -C 2 alkyl)-(C 3 -C 8 cycloalkyl), —(C 1 -C 6 alkyl)—O—(C 1 -C 3 alkyl), —C 2 -C 6 alkenyl, —C 2 -C 6 alkynyl; and
(E) C 3 -C 7 cycloalkyl, —C(O) (C 1 -C 4 alkyl), —SO 2 NR 10 R 11 , —C(O)NR 10 R 11 , or —SO 2 (C 1 -C 4 alkyl); and
PROT is a nitrogen protecting group;
the process comprising:
A) reducing a compound of the formula
with a reducing agent.
110 . A method according to claim 109 wherein the reducing agent is NaBH 4 , NaCNBH 3 , or hydrogen and a catalyst.
111 . A method according to claim 110 wherein the reducing agent is hydrogen and a catalyst.
112 . A method according to claim 111 wherein the hydrogenation is carried out at a pressure of from 1 atmosphere to about 100 psi.
113 . A method for preparing a compound of the formula
where
R is phenyl optionally substituted with 1, 2, 3, or 4 groups independently selected from:
(A) C 2 -C 6 alkyl optionally substituted with one, two or three substituents independently selected from C 1 -C 3 alkyl, halogen, hydroxy, thio, —NR 10 R 11 where R 10 and R 11 are independently hydrogen or C 2 -C 6 alkyl, cyano, trifluoromethyl, and C 2 -C 2 alkoxy,
(B) C 2 -C 6 alkenyl or C 2 -C 6 alkynyl,
(C) halogen, hydroxy, cyano, C 1 -C 6 alkoxy optionally substituted with 1, 2, or 3 fluoro,
(D) —NR 12 R 13 where at each occurrence R 12 and R 13 are the same or different and represent:
(a) —H,
(b) —C 2 -C 8 alkyl optionally substituted with one of:
(i) —OH,
(ii) —NH 2 ,
(iii) phenyl,
(c) —C 1 -C 8 alkyl optionally substituted with 1, 2, or 3 independently selected halogens,
(d) —C 3 -C 8 cycloalkyl, —(C 1 -C 2 alkyl)-(C 3 -C 8 cycloalkyl), —(C 1 -C 6 alkyl)—O—(C 1 -C 3 alkyl), —C 2 -C 6 alkenyl, —C 2 -C 6 alkynyl; and
(E) C 3 -C 7 cycloalkyl, —C(O)(C 1 -C 4 alkyl), —SO 2 NR 10 R 11 , —C(O)NR 10 R 11 , or —SO 2 (C 1 -C 4 alkyl);
R 2 is:
chloro, bromo, or
—Si(R 21 ) 3 where each R 21 is independently C 1 -C 5 alkyl,
—N(R 23 )(R 24 ) where R 23 and R 24 are the same or different and represent
C 1 -C 5 alkyl,
or where NR 23 R 24 represents piperidinyl, piperazinyl, or morpholinyl,
phenyl optionally substituted with 1, 2, or 3 of C 1 -C 2 alkyl, with the proviso that at least one of the R 21 groups is optionally substituted phenyl;
and
PROT is a nitrogen protecting group;
which comprises:
(a) forming a mixture of an ester of the formula
wherein
R 1 is selected from:
(I) C 1 -C 6 alkyl optionally substituted with one halogen;
(II) —CH 2 —CH═CH 2 ;
(III) phenyl optionally substituted with one nitro, halogen, or cyano; and
(IV) benzyl optionally substituted on phenyl with nitro, halogen, or cyano;
and R 2 CH 2 X 2 , where
R 2 is as defined above, and
X 2 is —Br or —I;
(b) adding a strong base having a pK b of greater than about 30 to the mixture from (a);
(c) acidifying the mixture of (b).
114 . A method for preparing a compound of the formula
where
R is phenyl optionally substituted with 1, 2, 3, or 4 groups independently selected from:
(A) C 1 -C 6 alkyl optionally substituted with one, two or three substituents independently selected from C 1 -C 3 alkyl, halogen, hydroxy, thio, —NR 10 R 11 where R 10 and R 11 are independently hydrogen or C 1 -C 6 alkyl, cyano, trifluoromethyl, and C 1 -C 3 alkoxy,
(B) C 2 -C 6 alkenyl or C 2 -C 6 alkynyl,
(C) halogen, hydroxy, cyano, C 1 -C 6 alkoxy optionally substituted with 1, 2, or 3 fluoro,
(D) —NR 12 R 13 where at each occurrence R 12 and R 13 are the same or different and represent:
(a) —H,
(b) —C 1 -C 8 alkyl optionally substituted with one of:
(i) —OH,
(ii) —NH 2 ,
(iii) phenyl,
(c) —C 1 -C 8 alkyl optionally substituted with 1, 2, or 3 independently selected halogens,
(d) —C 3 -C 8 cycloalkyl, —(C 1 -C 2 alkyl)—(C 3 -C 8 cycloalkyl), —(C 1 -C 6 alkyl)—O—(C 1 -C 3 alkyl), —C 2 -C 6 alkenyl, —C 2 -C 6 alkynyl; and
(E) C 3 -C 7 cycloalkyl, —C(O) (C 1 -C 4 alkyl) , —SO 2 NR 10 R 11 , —C(O)NR 10 R 11 , or —SO 2 (C 1 -C 4 alkyl);
R 2 is:
chloro, bromo, or
—Si(R 21 ) 3 where each R 21 is independently
C 1 -C 5 alkyl,
—N(R 23 ) (R 24 ) where R 23 and R 24 are the same or different and represent
C 1 -C 5 alkyl,
or where NR 23 R 24 represents piperidinyl, piperazinyl, or morpholinyl,
phenyl optionally substituted with 1, 2, or 3 of C 1 -C 2 alkyl, with the proviso that at least one of the R 21 groups is optionally substituted phenyl;
and
PROT is a nitrogen protecting group;
which comprises:
(a) forming a mixture of an acid R 2 —CH 2 —COOH and a base,
(b) treating the mixture of (a) with an ester of the formula
wherein R, and PROT are defined above, and
R 1 is selected from:
(I) C 1 -C 6 alkyl optionally substituted with one halogen;
(II) —CH 2 —CH═CH 2 ;
(III) phenyl optionally substituted with one nitro, halogen, or cyano; and
(IV) benzyl optionally substituted on phenyl with nitro, halogen, or cyano;
(c) acidifying the mixture from (b).
115 . A method according to claim 114 wherein, the base has a pK b 30 or greater.
116 . A method for preparing a compound of the formula
wherein
R is phenyl optionally substituted with 1, 2, 3, or 4 groups independently selected from:
(A) C 1 -C 6 alkyl optionally substituted with one, two or three substituents independently selected from C 1 -C 3 alkyl, halogen, hydroxy, thio, —NR 10 R 11 where R 10 and R 11 are independently hydrogen or C 1 -C 6 alkyl, cyano, trifluoromethyl, and C 1 -C 3 alkoxy,
(B) C 2 -C 6 alkenyl or C 2 -C 6 alkynyl,
(C) halogen, hydroxy, cyano, C 1 -C 6 alkoxy optionally substituted with 1, 2, or 3 fluoro,
(D) —NR 12 R 13 where at each occurrence R 12 and R 13 are the same or different and represent:
(a) —H,
(b) —C 1 -C 8 alkyl optionally substituted with one of:
(i) —OH,
(ii) —NH 2 ,
(iii) phenyl,
(c) —C 1 -C 8 alkyl optionally substituted with 1, 2, or 3 independently selected halogens,
(d) —C 3 -C 8 cycloalkyl, —(C 1 -C 2 alkyl)-(C 3 -C 8 cycloalkyl), —(C 1 -C 6 alkyl)—O—(C 1 -C 3 alkyl), —C 2 -C 6 alkenyl, —C 2 -C 6 alkynyl; and
(E) C 3 -C 7 cycloalkyl, —C(O) (C 1 -C 4 alkyl), —SO 2 NR 10 R 11 , —C(O)NR 10 R 11 , or —SO 2 (C 1 -C 4 alkyl);
R 2 is Cl or Br;
and
PROT is a nitrogen protecting group;
which comprises contacting a compound of the formula
wherein
X 1 is chloro, bromo, or imidazolyl;
with LiCH 2 Cl or LiCH 2 Br.
117 . A method for preparing a compound of the formula
wherein
X 1 is chloro, bromo, or imidazolyl;
R is phenyl optionally substituted with 1, 2, 3, or 4 groups independently selected from:
(A) C 1 -C 6 alkyl optionally substituted with one, two or three substituents independently selected from C 1 -C 3 alkyl, halogen, hydroxy, thio, —NR 10 R 11 where R 10 and R 11 are independently hydrogen or C 1 -C 6 alkyl, cyano, trifluoromethyl, and C 1 -C 3 alkoxy,
(B) C 2 -C 6 alkenyl or C 2 -C 6 alkynyl,
(C) halogen, hydroxy, cyano, C 1 -C 6 alkoxy optionally substituted with 1, 2, or 3 fluoro,
(D) —NR 12 R 13 where at each occurrence R 12 and R 13 are the same or different and represent:
(a) —H,
(b) —C 1 -C 8 alkyl optionally substituted with one of:
(i) —OH,
(ii) —NH 2 ,
(iii) phenyl,
(c) —C 1 -C 8 alkyl optionally substituted with 1, 2, or 3 independently selected halogens,
(d) —C 3 -C 8 cycloalkyl, —(C 1 -C 2 alkyl)-(C 3 -C 8 cycloalkyl), —(C 1 -C 6 alkyl)-O—(C 1 -C 3 alkyl), —C 2 -C 6 alkenyl, —C 2 -C 6 alkynyl; and
(E) C 3 -C 7 cycloalkyl, —C(O)(C 1 -C 4 alkyl), —SO 2 NR 10 R 11 , —C(O)NR 10 R 11 , or —SO 2 (C 1 -C 4 alkyl); and
PROT is a nitrogen protecting group;
which comprises
contacting a compound of the formula
with thionyl chloride, phosphorous trichloride, oxalyl chloride, phosphorous tribromide, triphenylphosphorous dibromide, oxalyl bromide, 1,2-phenylenetrichlorophosphate, 2,4,6-trichloro-1,3,5-triazine or carbonyldiimidazole.Join the waitlist — get patent alerts
Track US2010099898A1 — get alerts on status changes and closely related new filings.
We store only your email — no account needed. See our privacy policy.