US4216159A — Synthesis of 16-unsaturated pregnanes from 17-ket…

Claim 1

Independent Claim 324 words

A process for preparation of a compound of the formula: ##STR20## where R 6 is a hydrogen or fluorine atom or methyl group; where R 11 is a hydrogen atom, α--OR 11a or β--OR 11a ; where R 11a is a hydrogen atom or TMS with the proviso that when R 11 is --OR 11a , in ring C is a single bond; where R 16 is a hydrogen atom or methyl group; where R 21 is alkyl of 1 thru 5 carbon atoms or phenyl and where is a single or double bond which comprises: (1) reacting a compound of the formula: ##STR21## where R 3 is alkyl of 1 thru 5 carbon atoms; with the proviso that with the ketal the R 3 groups can be connected to form the ethylene ketal; where R 3' and R 3" are the same or different and are alkyl of 1 thru 5 carbon atoms; and where ˜ indicates R 16 is in either the α or β configuration, with a metalated olefin selected from the group consisting of a cis-trans mixture (VIa and VIb) or trans (VIb) compounds of the formula: ##STR22## where X is an oxygen or sulfur atom or --NR n -- ; whereR n is alkyl or 1 thru 3 carbon atoms; where Z is alkyl of 1 thru 5 carbon atoms; where Metal is selected from the group consisting of lithium, sodium, potassium, zinc, and magnesium and where R 20 is selected from the group consisting of a fluorine or chlorine atom or --NR.sub.α R.sub.β where R.sub.α and R.sub.β are the same or different and are alkyl of 1 thru 3 carbon atoms; to form a compound of the formula: ##STR23## (2) acid hydrolysis of the olefin (IIIa-IIIc) to form a 21 -aldehyde (IVa) of the formula: ##STR24## and (3) reaction of the 21-aldehyde (IVa) with a compound of the formula R 21 CO 2 ⊖ in an aprotic diluent.

Claim 2

Dependent Claim 324 words

A process for preparation of a compound of the formula: ##STR20## where R 6 is a hydrogen or fluorine atom or methyl group; where R 11 is a hydrogen atom, α--OR 11a or β--OR 11a ; where R 11a is a hydrogen atom or TMS with the proviso that when R 11 is --OR 11a , in ring C is a single bond; where R 16 is a hydrogen atom or methyl group; where R 21 is alkyl of 1 thru 5 carbon atoms or phenyl and where is a single or double bond which comprises: (1) reacting a compound of the formula: ##STR21## where R 3 is alkyl of 1 thru 5 carbon atoms; with the proviso that with the ketal the R 3 groups can be connected to form the ethylene ketal; where R 3' and R 3" are the same or different and are alkyl of 1 thru 5 carbon atoms; and where ˜ indicates R 16 is in either the α or β configuration, with a metalated olefin selected from the group consisting of a cis-trans mixture (VIa and VIb) or trans (VIb) compounds of the formula: ##STR22## where X is an oxygen or sulfur atom or --NR n -- ; whereR n is alkyl or 1 thru 3 carbon atoms; where Z is alkyl of 1 thru 5 carbon atoms; where Metal is selected from the group consisting of lithium, sodium, potassium, zinc, and magnesium and where R 20 is selected from the group consisting of a fluorine or chlorine atom or --NR.sub.α R.sub.β where R.sub.α and R.sub.β are the same or different and are alkyl of 1 thru 3 carbon atoms; to form a compound of the formula: ##STR23## (2) acid hydrolysis of the olefin (IIIa-IIIc) to form a 21 -aldehyde (IVa) of the formula: ##STR24## and (3) reaction of the 21-aldehyde (IVa) with a compound of the formula R 21 CO 2 ⊖ in an aprotic diluent.

Claim 3

Dependent Claim 15 words

A process according to claim 1 where R 6 is a hydrogen or fluorine atom.

Claim 4

Dependent Claim 14 words

A process according to claim 2 where the 16-unsaturated pregnane (Va) is 21-hydroxypregna-4,16-diene-3,20-dione 21-acetate.

Claim 5

Dependent Claim 21 words

A process according to claim 1 where in the C ring of the compound of formula Va is a double bond.

Claim 6

Dependent Claim 15 words

A process according to claim 4 where the 16-unsaturated pregnane (Va) is 21-hydroxypregna-4,9(11), 16-triene-3,20-dione 21-acetate.

Claim 7

Dependent Claim 17 words

A process according to claim 1 where the metalated olefin is the cis-trans mixture (VIa and VIb).

Claim 8

Dependent Claim 12 words

A process according to claim 6 where the metalated olefin is 2-chloro-2-lithio-1-ethoxyethylene.

Claim 9

Dependent Claim 15 words

A process according to claim 1 where the metalated olefin is the trans isomer (VIb).

Claim 10

Dependent Claim 12 words

A process according to claim 8 where the metalated olefin is trans-2-chloro-2-lithio-1-ethoxyethylene.

Claim 11

Dependent Claim 22 words

A process according to claim 1 where in the metalated olefin the Metal is lithium and R 20 is a chlorine atom.

Claim 12

Dependent Claim 18 words

A process according to claim 1 where step (1) is performed at less than or equal to -25°.

Claim 13

Dependent Claim 14 words

A process according to claim 1 where R 21 CO 2 .sup.⊖ is acetate.

Claim 14

Dependent Claim 20 words

A process according to claim 1 where the aprotic diluent is selected from the group consisting of DMF or DMSO.

Claim 15

Dependent Claim 56 words

A process for preparation of 21-hydroxypregna-4,9(11), 16-triene-3,20-dione 21-acetate which comprises: (1) reacting 3-hydroxyandrosta-3,5,9(11)-triene-17-one 3-methyl ether with a cis-trans mixture of 2-chloro-2-lithio-1-ethoxyethylene to give cis and trans 20chloro-3,17β,21-trihydroxy-17α-pregna-3,5,9(11),20-tetraene 3-methyl-21-ethyl ether; (2) hydrolysis of the product of step (1) with acid to give 20-chloropregna-4,9(11), 17(20)-trien-3-one-21-al (IVa) and (3) reacting the product of step (2) with acetate in DMF.

Claim 16

Dependent Claim 56 words

A process for preparation of 21-hydroxypregna-4,9(11), 16-triene-3,20-dione 21-acetate which comprises: (1) reacting 3-hydroxyandrosta-3,5,9(11)-triene-17-one 3-methyl ether with a cis-trans mixture of 2-chloro-2-lithio-1-ethoxyethylene to give cis and trans 20chloro-3,17β,21-trihydroxy-17α-pregna-3,5,9(11),20-tetraene 3-methyl-21-ethyl ether; (2) hydrolysis of the product of step (1) with acid to give 20-chloropregna-4,9(11), 17(20)-trien-3-one-21-al (IVa) and (3) reacting the product of step (2) with acetate in DMF.

Claim 17

Dependent Claim 49 words

A process for preparation of 21-hydroxypregna-4,9(11),16-triene-3,20-dione 21-acetate which comprises: (1) reacting 3-hydroxyandrosta-3,5,9(11)-triene-17-one 3-methyl ether with trans-2-chloro-2-lithio-1-ethoxyethylene to give trans 20-chloro-3,17β,21-trihydroxy-17α-pregna-3,5,9(11),20-tetraene 3-methyl-21-ethyl ether; (2) hydrolysis of the product of step (1) with acid to give 20-chloropregna-4,9(11), 17(20trien-3-one-21-al (IVa) and (3) reacting the product of step (2) with acetate in DMF.

Claim 18

Dependent Claim 49 words

A process for preparation of 21-hydroxypregna-4,9(11),16-triene-3,20-dione 21-acetate which comprises: (1) reacting 3-hydroxyandrosta-3,5,9(11)-triene-17-one 3-methyl ether with trans-2-chloro-2-lithio-1-ethoxyethylene to give trans 20-chloro-3,17β,21-trihydroxy-17α-pregna-3,5,9(11),20-tetraene 3-methyl-21-ethyl ether; (2) hydrolysis of the product of step (1) with acid to give 20-chloropregna-4,9(11), 17(20trien-3-one-21-al (IVa) and (3) reacting the product of step (2) with acetate in DMF.

Claim 19

Dependent Claim 91 words

A process for the preparation of both geometrical isomers at C 20 of a compound of the formula: ##STR25## which comprises: (1) reacting a compound of the formula: ##STR26## with a metalated olefin selected from the group consisting of a cis-trans mixture (VIa and VIb) or trans (VIb) compound of the formula: ##STR27## and (2) acid hydrolysis where R 3 , R 3 ' , R 3 " , R 6 , R 11 , R 16 , R 20 , X, Z, Metal, ˜ and are defined in claim 1.

Claim 20

Dependent Claim 15 words

A process according to claim 16 where R 6 is a hydrogen or fluorine atom.

Claim 21

Dependent Claim 12 words

A process according to claim 17 where the 21-aldehyde (IVa) is 20-chloropregna-4,16-diene-3-one-21-al.

Claim 22

Dependent Claim 15 words

A process according to claim 16 where in the C ring is a double bond.

Claim 23

Dependent Claim 13 words

A process according to claim 19 where the 21-aldehyde (IVa) is 20-chloropregna-4,9(11), 16-triene-3-one-21-al.

Claim 24

Dependent Claim 17 words

A process according to claim 16 where the metalated olefin is the cis-trans mixture (VIa and VIb).

Claim 25

Dependent Claim 12 words

A process according to claim 21 where the metalated olefin is 2-chloro-2-lithio-1-ethoxyethylene.

Claim 26

Dependent Claim 15 words

A process according to claim 16 where the metalated olefin is the trans isomer (VIb).

Claim 27

Dependent Claim 12 words

A process according to claim 23 where the metalated olefin is trans-2-chloro-2-lithio-1-ethoxyethylene.

Claim 28

Dependent Claim 22 words

A process according to claim 16 where in the metalated olefin the Metal is lithium and R 20 is a chlorine atom.

Claim 29

Dependent Claim 18 words

A process according to claim 16 where step (I) is performed at less than or equal to -25°.

Claim 30

Dependent Claim 157 words

A process for the preparation of a compound of the formula: ##STR28## and the cis C 20-21 isomer thereof where R 17 is a hydrogen atom, alkyl of 1 thru 3 carbon atoms or an acyl group of 2 thru 5 carbon atoms which comprises: (1) reacting the corresponding C-3 protected compound of the formula: ##STR29## with a metalated olefin selected from the group consisting of a cis-trans mixture (VIa and VIb) or trans (VIb) compound of the formula: ##STR30## and (2) quenching the reaction with a compound of the formula R 17a -W, (R 17a CO) 2 O, R 17a COM or water; where R 17a is alkyl of 1 thru 3 carbon atoms; where W is a bromine or iodine atom where M is a chlorine or bromine atom; where R 3 , R 6 , R 11 , R 16 , R 20 , X, Z, ˜, and Metal are defined in claim 1.

Claim 31

Dependent Claim 15 words

A process according to claim 27 where R 6 is a hydrogen or fluorine atom.

Claim 32

Dependent Claim 13 words

A process according to claim 28 where the steroid (IIIa) is 20-chloro-3,17β,21-trihydroxypregna-3,5,20-triene-3,17-dimethyl-21-ethyl ether.

Claim 33

Dependent Claim 23 words

A process according to claim 27 where the in the C ring of the compound IIIa, IIIb or IIIc is a double bond.

Claim 34

Dependent Claim 15 words

A process according to claim 30 where the steroid (IIIa) is 20-chloro-3,17β,20-trihydroxypregna-3,5,9(11), 20-tetraene 3,17-dimethyl-21-ethyl ether.

Claim 35

Dependent Claim 17 words

A process according to claim 27 where the metalated olefin is the cis-trans mixture (VIa and VIb).

Claim 36

Dependent Claim 12 words

A process according to claim 32 where the metalated olefin is 2-chloro-2-lithio-1-ethoxyethylene.

Claim 37

Dependent Claim 15 words

A process according to claim 27 where the metalated olefin is the trans isomer (IVb).

Claim 38

Dependent Claim 12 words

A process according to claim 34 where the metalated olefin is trans-2-chloro-2-lithio-1-ethoxyethylene.

Claim 39

Dependent Claim 22 words

A process according to claim 27 where in the metalated olefin the Metal is lithium and R 20 is a chlorine atom.

Claim 40

Dependent Claim 19 words

A process according to claim 27 where the step (I) is performed at less than or equal to -25°.

Claim 41

Dependent Claim 78 words

A process for the preparation of both geometrical isomers at C 20 of a compound of the formula: ##STR31## which comprises acid hydrolysis of a compound of the formula: ##STR32## or the cis C 20-21 isomer thereof where R 3 , R 3 ', R 3 ", R 6 , R 11 , R 16 , R 20 , X, Z, ˜ and a are defined in claim 1 and where R 17 is defined in claim 27.

Claim 42

Dependent Claim 14 words

A process according to claim 38 where the compound of formula (IVa) is 20-chloropregna-4,9(11),17(20)-triene-3-one-21-al.

Claim 43

Dependent Claim 122 words

A process for preparation of a compound of the formula: ##STR33## which comprises: (1) reacting a compound of the formula: ##STR34## with a metalated olefin selected from the group consisting of a cis-trans mixture (VIa and VIb) or trans (VIb) compounds of the formula: ##STR35## to give a compound of the formula: ##STR36## (2) acid hydrolysis of the olefin (IIId or IIIe) to give a 21-aldehyde (IVb) of the formula: ##STR37## and (3) reaction of the 21-aldehyde (IVb) with a compound of the formula R 21 CO 2 .sup.⊖ in an aprotic diluent where R 3 , R 3 .spsb.', R 3 .spsb.", R 6 , R 11 , R 16 , R 21 , ˜ and are defined in claim 1.

Claim 44

Dependent Claim 15 words

A process according to claim 40 where R 6 is a hydrogen or fluorine atom.

Claim 45

Dependent Claim 18 words

A process according to claim 40 where in the C ring of compound Vb is a double bond.

Claim 46

Dependent Claim 14 words

A process according to claim 42 where the 16-unsaturated steroid (Vb) is 21-hydroxypregna-1,4,9(11),16-tetraene-3,20-dione 21-acetate.

Claim 47

Dependent Claim 17 words

A process according to claim 40 where the metalated olefin is the cis-trans mixture (VIa and VIb).

Claim 48

Dependent Claim 12 words

A process according to claim 44 where the metalated olefin is 2-chloro-2-lithio-1-ethoxyethylene.

Claim 49

Dependent Claim 15 words

A process according to claim 40 where the metalated olefin is the trans isomer (VIb).

Claim 50

Dependent Claim 12 words

A process according to claim 46 where the metalated olefin is trans-2-chloro-2-lithio-3-ethoxyethylene.

Claim 51

Dependent Claim 22 words

A process according to claim 40 where in the metalated olefin the Metal is lithium and R 20 is a chlorine atom.

Claim 52

Dependent Claim 18 words

A process according to claim 40 where step 1) is performed at less than or equal to -25°.

Claim 53

Dependent Claim 14 words

A process according to claim 40 where R 21 CO 2 .sup.⊖ is acetate.

Claim 54

Dependent Claim 20 words

A process according to claim 40 where the aprotic diluent is selected from the group consisting of DMF or DMSO.

Claim 55

Dependent Claim 53 words

A process for preparation of 21-hydroxypregna-1,4,9(11),16-tetraene-3,20-dione 21-acetate which comprises: (1) reacting androsta-1,3,5,9(11)-tetraene-17-one-3-diethylenamine with a cis-trans mixture of 2-chloro-2-lithio-1-ethoxyethylene to give a compound of the formula: ##STR38## (2) hydrolysis of the product of step (1) with acid to give 20-chloropregna 1,4,9(11),17(20)-tetraen-3-one-21-al (IVb) and (3) reacting the product of step (2) with acetate in DMF.

Claim 56

Dependent Claim 53 words

A process for preparation of 21-hydroxypregna-1,4,9(11),16-tetraene-3,20-dione 21-acetate which comprises: (1) reacting androsta-1,3,5,9(11)-tetraene-17-one-3-diethylenamine with a cis-trans mixture of 2-chloro-2-lithio-1-ethoxyethylene to give a compound of the formula: ##STR38## (2) hydrolysis of the product of step (1) with acid to give 20-chloropregna 1,4,9(11),17(20)-tetraen-3-one-21-al (IVb) and (3) reacting the product of step (2) with acetate in DMF.

Claim 57

Dependent Claim 48 words

A process for preparation of 21-hydroxypregna-1,4,9(11),16-tetraene-3,20-dione 21-acetate which comprises: (1) reacting androsta-1,3,5,9(11)-tetraene-17-one-3-diethylenamine with trans-2-chloro-2-lithio-1-ethoxyethylene to give a compound of the formula: ##STR39## (2) hydrolysis of the product of step (1) with acid to give 20-chloropregna-1,4,9(11),17(20)-tetraen-3-one-21-al (IVb) and (3) reacting the product of step (2) with acetate in DMF,

Claim 58

Dependent Claim 48 words

A process for preparation of 21-hydroxypregna-1,4,9(11),16-tetraene-3,20-dione 21-acetate which comprises: (1) reacting androsta-1,3,5,9(11)-tetraene-17-one-3-diethylenamine with trans-2-chloro-2-lithio-1-ethoxyethylene to give a compound of the formula: ##STR39## (2) hydrolysis of the product of step (1) with acid to give 20-chloropregna-1,4,9(11),17(20)-tetraen-3-one-21-al (IVb) and (3) reacting the product of step (2) with acetate in DMF,

Claim 59

Dependent Claim 89 words

A process for the preparation of both geometrical isomers at C 20 of a compound of the formula: ##STR40## which comprises: (1) reacting a compound of the formula: ##STR41## with a metalated olefin selected from the group consisting of a cis-trans mixture (VIa and VIb) or trans (VIb) compound of the formula: ##STR42## and (2) acid hydrolysis where R 3 , R 3 ', R 3 ", R 6 , R 11 , R 16 , R 20 , X, Z, Metal, ˜ and are defined in claim 1.

Claim 60

Dependent Claim 15 words

A process according to claim 54 where R 6 is a hydrogen or fluorine atom.

Claim 61

Dependent Claim 15 words

A process according to claim 54 where in the C ring is a double bond.

Claim 62

Dependent Claim 13 words

A process according to claim 56 where the 21-aldehyde (IVb) is 20-chloropregna-1,4,9(11),17(20)-tetraene-3-one 21-al.

Claim 63

Dependent Claim 17 words

A process according to claim 54 where the metalated olefin is the cis-trans mixture (VIa and VIb).

Claim 64

Dependent Claim 12 words

A process according to claim 58 where the metalated olefin is 2-chloro-2-lithio-1-ethoxyethylene.

Claim 65

Dependent Claim 15 words

A process according to claim 54 where the metalated olefin is the trans isomer (IVb).

Claim 66

Dependent Claim 12 words

A process according to claim 60 where the metalated olefin is trans-2-chloro-2-lithio-3-ethoxyethylene.

Claim 67

Dependent Claim 18 words

A process according to claim 54 where the Metal is lithium and R 20 is a chlorine atom.

Claim 68

Dependent Claim 18 words

A process according to claim 54 where step (1) is performed at less than or equal to -25°.

Claim 69

Dependent Claim 135 words

A process for the preparation of a compound of the formula: ##STR43## and the cis C 20-21 isomer thereof which comprises: (1) reacting the corresponding C 3 protected compound of the formula: ##STR44## with a metalated olefin selected from the group consisting of a cis-trans mixture (VIa and VIb) or trans (VIb) compound of the formula: ##STR45## and (2) quenching the reaction with a compound of the formula R 17a -W, (R 17a CO) 2 O, R 17a COM; where R 17a is alkyl of 1 thru 3 carbon atoms; where R 3 , R 3 ', R 3 ", R 6 , R 11 , R 16 , R 20 , X, Z, ˜, and Metal are defined in claim 1, and where R 17 , M and W were defined in claim 27.

Claim 70

Dependent Claim 15 words

A process according to claim 64 where R 6 is a hydrogen or fluorine atom.

Claim 71

Dependent Claim 16 words

A process according to claim 64 where the in the C ring is a double bond.

Claim 72

Dependent Claim 15 words

A process according to claim 66 where the steroid (IIId) is 20-chloro-17β,21-dihydroxypregna-1,3,5,9(11),20-pentaene 17-methyl-21-ethyl ether 3-diethylenamine.

Claim 73

Dependent Claim 17 words

A process according to claim 64 where the metalated olefin is the cis-trans mixture (VIa and VIb).

Claim 74

Dependent Claim 12 words

A process according to claim 68 where the metalated olefin is 2-chloro-2-lithio-1-ethoxyethylene.

Claim 75

Dependent Claim 15 words

A process according to claim 64 where the metalated olefin is the trans isomer (VIb).

Claim 76

Dependent Claim 12 words

A process according to claim 70 where the metalated olefin is trans-2-chloro-2-lithio-1-ethoxyethylene.

Claim 77

Dependent Claim 18 words

A process according to claim 64 where the Metal is lithium and R 20 is a chlorine atom.

Claim 78

Dependent Claim 19 words

A process according to claim 64 where the step (1) is performed at less than or equal to -25°.

Claim 79

Dependent Claim 77 words

A process for the preparation of both geometrical isomers at C 20 of a compound of the formula: ##STR46## which comprises acid hydrolysis of a compound of the formula: ##STR47## or the cis C 20-21 isomer thereof where R 3 , R 3 ', R 3 ", R 6 , R 11 , R 16 , R 20 , X, Z, ˜, and are defined in claim 1 and where R 17 is defined in claim 27.

Claim 80

Dependent Claim 14 words

A process according to claim 74 where the compound of formula (IVb) is 20-chloropregna-1,4,9(11),17(20)-tetraene-3-one-21-al.

Claim 81

Dependent Claim 34 words

A compound of the formula: ##STR48## and the geometrical isomer thereof at C 20 where R 6 , R 11 , R 16 , R 20 , ˜ and are defined in claim 1.

Claim 82

Dependent Claim 14 words

A compound according to claim 76 where in ring A is a single bond.

Claim 83

Dependent Claim 15 words

A compound according to claim 76 where R 6 is a hydrogen or fluorine atom.

Claim 84

Dependent Claim 13 words

A compound according to claim 76 where R 20 is a chlorine atom.

Claim 85

Dependent Claim 14 words

A compound according to claim 76 where in ring A is a double bond.

Claim 86

Dependent Claim 13 words

A compound according to claim 80 where R 20 is a chloring atom.

Claim 87

Dependent Claim 9 words

a compound according to claim 81 which is 20-chloropregna-1,4,9(11),17(20)-tetraene-3-one-21-al.

Claim 88

Dependent Claim 14 words

A compound according to claim 76 where in ring C is a double bond.

Claim 89

Dependent Claim 14 words

A compound according to claim 83 where in ring A is a single bond.

Claim 90

Dependent Claim 15 words

A compound according to claim 84 where R 6 is a hydrogen or fluorine atom.

Claim 91

Dependent Claim 13 words

A compound according to claim 85 where R 20 is a chlorine atom.

Claim 92

Dependent Claim 9 words

A compound according to claim 86 which is 20-chloropregna-4,9(11),17(20)-triene-3-one-21-al.

Claim 93

Dependent Claim 47 words

A compound of the formula: ##STR49## and the C 20-21 cis isomer thereof where R 3 , R 11 , R 6 , R 16 , R 20 , X, Z, ˜, and are defined in claim 1 and where R 17 is defined in claim 27.

Claim 94

Dependent Claim 25 words

A compound according to claim 88 where R 3 is methyl or ethyl, R 20 is a chlorine atom and X is an oxygen atom.

Claim 95

Dependent Claim 11 words

A compound according to claim 89 which is 20-chloro-3,17β,21-trihydroxypregna-3,5,9(11),20-tetraene 3,17-dimethyl-21-ethyl ether.

Claim 96

Dependent Claim 11 words

A compound according to claim 89 which is 20-chloro-3,17β,21-trihydroxypregna-3,5,9(11),20-tetraene 3-methyl-21-ethyl ether.

Claim 97

Dependent Claim 11 words

A compound according to claim 89 which is 20-chloro-3,17β,21-trihydroxypregna-3,5,20-triene 3,17-dimethyl-21-ethyl ether.

Claim 98

Dependent Claim 50 words

A compound of the formula: ##STR50## and the C 20-21 cis isomer thereof where R 3 ', R 3 ", R 6 , R 11 , R 16 , R 20 , X, Z, ˜ and are defined in claim 1 and where R 17 is defined in claim 27.

Claim 99

Dependent Claim 47 words

A compound of the formula: ##STR51## and the C 20-21 cis isomer thereof where R 3 , R 6 , R 11 , R 16 , R 20 , X, Z, ˜ and are defined in claim 1 and where R 17 is defined in claim 27.

Claim 100

Dependent Claim 50 words

A compound of the formula: ##STR52## and the C 20-21 cis isomer thereof where R 3 ', R 3 ", R 6 , R 11 , R 16 , R 20 , X, Z, ˜ and are defined in claim 1; and where R 17 is defined in claim 27.

Claim 101

Dependent Claim 30 words

A compound according to claim 95 where R 3 ' and R 3 " are methyl or ethyl, R 20 is a chlorine atom, and X is an oxygen atom.

Claim 102

Dependent Claim 12 words

A compound according to claim 96 which is 20-chloro-17β,21-dihydroxypregna-1,3,5,9(11),20-pentaene 17-methyl-21-ethyl ether 3-diethylenamine.

Claim 103

Dependent Claim 47 words

A compound of the formula: ##STR53## and the C 20-21 cis isomer thereof where R 3 , R 6 , R 11 , R 16 , R 20 , X, Z, ˜ and are defined in claim 1 and where R 17 is defined in claim 27.

Claim 104

Dependent Claim 36 words

A compound of the formula: ##STR54## and the C 20-21 isomer thereof where R 3 , R 6 , R 11 , R 16 , R 20 , X and Z are defined in claim 1.

Claim 105

Dependent Claim 25 words

A compound according to claim 99 where R 3 is methyl or ethyl, R 20 is a chlorine atom and X is an oxygen atom.

Claim 106

Dependent Claim 11 words

A compound according to claim 100 which is 20-chloro--3,21-dihydroxypregna-3,5,9(11),16,20-pentaene 3-methyl-21-ethyl ether.

Claim 107

Dependent Claim 39 words

A compound of the formula: ##STR55## and the C 20-21 isomer thereof where R 3 ', R 3 ", R 6 , R 11 , R 16 , R 20 , X and Z are defined in claim 1.

Claim 108

Dependent Claim 30 words

A compound according to claim 102 where R 3 ' and R 3 " are methyl or ethyl, R 20 is a chlorine atom and X is an oxygen atom.

Claim 109

Dependent Claim 11 words

A compound according to claim 103 which is 20-chloro-21-hydroxypregna-1,3,5,9(11),16,20-hexaene-21-ethyl ether 3-diethylenamine.

Claim 110

Dependent Claim 39 words

A process for the preparation of 20-chloropregna-4,9(11),17(20)-triene-3-one-21-al which comprises: (1) reacting 3-hydroxyandrosta-3,5,9(11)-triene-17-one 3-methyl ether with a cis-trans mixture of 2-chloro-2-lithio-1-ethoxyethylene to give cis and trans 20-chloro-3,17β,21-trihydroxy-17α-pregna-3,5,9(11),20-tetraene 3-methyl-21-ethyl ether and (2) hydrolysis of the product of step (1) with acid.

Claim 111

Dependent Claim 39 words

A process for the preparation of 20-chloropregna-4,9(11),17(20)-triene-3-one-21-al which comprises: (1) reacting 3-hydroxyandrosta-3,5,9(11)-triene-17-one 3-methyl ether with a cis-trans mixture of 2-chloro-2-lithio-1-ethoxyethylene to give cis and trans 20-chloro-3,17β,21-trihydroxy-17α-pregna-3,5,9(11),20-tetraene 3-methyl-21-ethyl ether and (2) hydrolysis of the product of step (1) with acid.

Claim 112

Dependent Claim 31 words

A process for the preparation of 20-chloropregna-4,9(11),17(20)-triene-3-one-21-al which comprises: (1) reacting 3-hydroxyandrosta-3,5,9(11)-triene-17-one 3-methyl ether with trans-2-chloro-2-lithio-1-ethoxyethylene trans 20-chloro-3,17β,21-trihydroxy-17α-pregna-3,5,9(11),20-tetraene 3-methyl-21-ethyl ether and (2) hydrolysis of the product of step (1) with acid.

Claim 113

Dependent Claim 31 words

A process for the preparation of 20-chloropregna-4,9(11),17(20)-triene-3-one-21-al which comprises: (1) reacting 3-hydroxyandrosta-3,5,9(11)-triene-17-one 3-methyl ether with trans-2-chloro-2-lithio-1-ethoxyethylene trans 20-chloro-3,17β,21-trihydroxy-17α-pregna-3,5,9(11),20-tetraene 3-methyl-21-ethyl ether and (2) hydrolysis of the product of step (1) with acid.

Claim 114

Dependent Claim 1 words

20-Bromopregna-4,9(11),17(20)-trien-3-one-al.

Claim 115

Dependent Claim 1 words

20-Bromopregna-4,9(11),17(20)-trien-3-one-al.

Claim 116

Dependent Claim 39 words

A process for the preparation of a compound of the formula: ##STR56## which comprises reacting 20-bromopregna-4,9(11),17(20)-trien-3-one-21-al with a compound of the formula R 21 CO 2 ⊖ in an aprotic diluent where R 21 is defined in claim 1.

Claim 117

Dependent Claim 11 words

A process according to claim 108 where R 21 is methyl.

Claim 118

Dependent Claim 20 words

A process according to claim 108 where the aprotic diluent is selected from the group consisting of DMF or DMSO.

Claim 119

Dependent Claim 44 words

A process for the preparation of a compound of the formula: ##STR57## which comprises reacting a compound of the formula: ##STR58## with a compound of the formula R 21 CO 2 ⊖ in an aprotic diluent where R 21 is defined in claim 1.

Claim 120

Dependent Claim 18 words

A process according to claim 111 where the compound of formula V is a compound of formula Va.

Claim 121

Dependent Claim 18 words

A process according to claim 111 where the compound of formula V is a compound of formula Vb.

Claim 122

Dependent Claim 11 words

A process according to claim 111 where R 21 is methyl.

Claim 123

Dependent Claim 20 words

A process according to claim 111 where the aprotic diluent is selected from the group consisting of DMF or DMSO.

Claim 124

Dependent Claim 12 words

A process according to claim 115 where the aprotic diluent is DMF.

Claim 125

Dependent Claim 15 words

A process according to claim 111 where the compound of formula (V) is 21-hydroxypregna-4,9(11),16-trien-3,20-dione 21-acetate.

Claim 126

Dependent Claim 16 words

A process for the preparation of 21-hydroxypregna-4,9(11),16-triene-3,20-dione 21-acetate which comprises reacting 20-chloropregna-4,9(11),17(20)-trien-3-one-21-al with acetate in DMF.

Claim 127

Dependent Claim 16 words

A process for the preparation of 21-hydroxypregna-4,9(11),16-triene-3,20-dione 21-acetate which comprises reacting 20-chloropregna-4,9(11),17(20)-trien-3-one-21-al with acetate in DMF.

Annuity Stage	Window Opens	Payment Deadline	Surcharge Period Until	Estimated Fee	Status
3.5 Years (Year 4)	1983-08-05	1984-02-04	1984-08-05	$2000.00	Window Closed / Lapsed
7.5 Years (Year 8)	1987-08-05	1988-02-04	1988-08-05	$3760.00	Window Closed / Lapsed
11.5 Years (Year 12)	1991-08-05	1992-02-04	1992-08-05	$7700.00	Window Closed / Lapsed

Synthesis of 16-unsaturated pregnanes from 17-keto steroids

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