Dehydrogenation process (original) (raw)

CA1331601C - Dehydrogenation process - Google Patents

Dehydrogenation process

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Publication number

CA1331601C

CA1331601C CA000570228A CA570228A CA1331601C CA 1331601 C CA1331601 C CA 1331601C CA 000570228 A CA000570228 A CA 000570228A CA 570228 A CA570228 A CA 570228A CA 1331601 C CA1331601 C CA 1331601C

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CA

Canada

Prior art keywords

hydrogen

alkyl

methyl

alk

compound

Prior art date

1987-06-29

Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)

Expired - Lifetime

Application number

CA000570228A

Other languages

French (fr)

Inventor

Apurba Bhattacharya

Alan W. Douglas

Edward J. Grabowski

Ulf H. Dolling

Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)

Merck Sharp and Dohme LLC

Original Assignee

Merck and Co Inc

Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)

1987-06-29

Filing date

1988-06-23

Publication date

1994-08-23

1988-06-23 Application filed by Merck and Co Inc filed Critical Merck and Co Inc

1994-08-23 Application granted granted Critical

1994-08-23 Publication of CA1331601C publication Critical patent/CA1331601C/en

2011-08-23 Anticipated expiration legal-status Critical

Status Expired - Lifetime legal-status Critical Current

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Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07J—STEROIDS
  • C07J75/00—Processes for the preparation of steroids in general
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07J—STEROIDS
  • C07J73/00—Steroids in which the cyclopenta[a]hydrophenanthrene skeleton has been modified by substitution of one or two carbon atoms by hetero atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07J—STEROIDS
  • C07J73/00—Steroids in which the cyclopenta[a]hydrophenanthrene skeleton has been modified by substitution of one or two carbon atoms by hetero atoms
  • C07J73/001—Steroids in which the cyclopenta[a]hydrophenanthrene skeleton has been modified by substitution of one or two carbon atoms by hetero atoms by one hetero atom
  • C07J73/005—Steroids in which the cyclopenta[a]hydrophenanthrene skeleton has been modified by substitution of one or two carbon atoms by hetero atoms by one hetero atom by nitrogen as hetero atom

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• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Health & Medical Sciences (AREA)
• General Health & Medical Sciences (AREA)
• Steroid Compounds (AREA)
• Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
• Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
• Transition And Organic Metals Composition Catalysts For Addition Polymerization (AREA)
• Catalysts (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Saccharide Compounds (AREA)

Abstract

(1) ABSTRACT OF THE INVENTION
A process for dehydrogenating a compound of the formula (I) (2) (II) (III) which comprises reacting the compound with a silylating agent in the presence of a quinone to introduce a.DELTA.1 double bond. Novel intermediates are compounds of the formula (3) - i - (I) wherein:
Q is absent or is or or or -OH
-OH
where R4 is methyl, C1-8 straight or branched chain alkyl, C3-6 cycloalkyl, phenyl, or combinations thereof; and R14 is hydrogen, C1-6 alkyl, C1-6 straight or branched chain alkoxy, halo, nitro or cyano.

Description

0236/CMCl TITLE OF THE INVENTION
DEHYDROGENATION PROCESS

BACKGROUND OF THE INVENTION
The present lnvention is concerned with a process for dehydrogenating compounds, particularly 3-oxo-4-azasteroids, to prepare corresponding ~l compounds and novel intermediates utilized in the process.
Heretofore, azasteroids have been dehydrogenated to introduce a 1 double bond by means of benzene seleninic anhydride oxidation in which the saturated compound was heated with the benzene seleninic anhydride in refluxing chlorobenzene.
Back, T. G., J. Org. Chem. 46: 1442 (1981); Rasmussen et al., J. Med. Chem. 29: 2298 (1986). Ad~itionally, æulfoxide elimination has been a process used to accomplish the dehydrogenation. See U.S. Patent 4,377,584, 4,220,775 and EP application 85301122.9 (published September 18, 1985). However, these reactions have been found to qive poor yields, 13316~1 0236/CMCl - 3 - 17474Y

with a high degreQ of impUritiQs and one rQquires the USQ of a selenium catalyst which is very expQnsivQ
and is quite toxic.
It has also beQn known to dehydrogenate a 3-oxo-4-a~alactam by a complicated 5-step process which involves a sulfenate intermediate. See Magnus et al., J. Am. Chem. Soc. 1986: 108 221-227. How-ever, the process o~ the present invention provides a versatile single-pot process for the direct introduc-tion of a ~1 double bond into 3-oxo-4-azasteroids in high yields and without the attendant toxicity and impurity problems associated with the prior art.
The process of the present invention is a single-pot silyation mediated quinone oxidation of lactams, lactones and 3-keto-4-azasteroids to the corresponding~l double bond compound. The present invention provides a unique way to dehydrogenate a wide variety of compounds while avoiding the disadvantages of the prior art methods of effecting such transformations. The disadvantages overcome by the present invention include complicated multi-step processes, poor yields, unwanted by-products and the use of toxic selenium catalysts.

SUMMARY OF THE INVENTION
The present invention provides a process for dehydrogenating a compound of the formula .. . .

0236/CMCl - 4 - 17474Y

~ R ~:

B~ R~

0 ~ I) A~

c II) ( III) where Formula (I) may alternatively have the structure of partial Formulas (II) and/or (III);
wherein, A i8 (1)-CH2-CH2-;
i ; ; . , ~
(2) CH3 :.
-CH-CH2-;

: B is (1) 1331~1 0236/CMCl - 5 - 174~4Y

o x where X is N, O or CH2; and Rl is absent or is (a) hydrogen;
(b) methyl or ethyl;
(c) NR2R3 where R2 and R3 are hydrogen or methyl; or (d) cyano; or (2) (a) ( R4) 3 S10 / N/

(b) ; ~ . .

C R4) 3 S 10 o (c) c ( R4) 3 S10 CH2 ~ .

~331601 0236/CMCl - 6 - 17474Y

(d) !

~F~ )3 SiO CH

(e) c .
0 (R4)3 SiO N
Rl where R4 is Cl 8 straight or branched chain alkyl, for example, methyl; C3 6 cycloalkyl, phenyl or combinations 5 thereof;

R' is hydrogen or methyl;
R" is hydrogen or B-methyl;
R"' is hydrogen, B methyl or hydroxyl; ~:~
:~:
Z is . :
~ hydrogen and a-hydroxyl;
(2) a-hydrogen or a-hydroxyl and (a) -Alk-C-R8, where ~lk is present or absent and is a straight or branched hydrocarbon chain of 1 to 12 carbon atoms; and R8 is, ~i) hydroqen, (ii) hydroxyl, (iii) C1_12 alkyl, C
~.... .

1331~01 0236/CMCl - 7 - 17474Y

(iv) NR9R10, where R9 and R10 are each independently selected from hydrogen;
C1_12 straight or branched chain alkyl;
Cl_l2 straight or branched chain alkyl having a hydrogen substituted with a hydroxy, carboxylic acid or Cl_4 alkyl ester; C3-6 cycloalkyl; phenyl; or R9 and R10 taken together with the nitrogen to which they are attached represent a 5-6 membered saturated ring comprising up to one other heteroatom selected from oxygen and nitrogen; or (v) ORll, where Rll is M, where M is ~5 hydrogen or alkali metal, or Cl_lg straight or branched chain alkyl;
benzyl; or (b) -(Alk)-OR12, where Alk i~ present or absent and has the same meaning as above; and R12 iS
(i) phenyl Cl_6 alkylcarbonyl, (ii) Cs_l~ cycloalkylcarbonyl, (iii) benzoyl, or (iv) Cl_lg alkoxycarbonyl;
(v) hydrogen;

(3) -CH-Alk-C-R8 1331~1 0236/CMCl - 8 - 17474Y

or-CH-Alk-OR12, where Alk is present or absent and has the same meaning as above, and R8 and R12 ha~e the same meaning as above, and R12 is also hydrogen or Cl_20 alkylcarbonyl;
(4) r~ ~
o\

where the dashed bond replaces the 17a hydrogen;

(5) a-hydrogen and NHC_R13, where R13 is, (a) C1_12 alkyl: or (b) NR9R10;

(6) a-hydrogen and cyano; or (7) a-hydrogen and tetrazolyl;
which comprises reacting the compound with a silylating agent in the presence of a quinone to introduce a ~1 double bond.

133~

Thc azasteroid compo~ds prepared by the processes of the present invention are testosterone-5a-reductase inhibitors useful for treating the hyperandrogenic conditions of acne vulgaris, seborrhea, female hirsutism, androgenic alopeci~
including male pattern alopecia, prostatic carcinoma and benign prostatic hypertrophy by topical or systemic administration.
Novel silylated intermediate compounds useful in preparing the corresponding ~1 compound are also an important part of the present invention.

DETAILED DESCRIPTION OF THE INVENTION
Generally, the process of the invention involves treatment of the saturated starting lactam, lactone or azasteroid with a silylating agent in the presence of a quinone. A number of silylating agents capable of sily-lating lactams, lactones and azasteroids can be used.
For example, bistrimethylsilylacetamide, bistrimethyl-silyltrihaloacetamide, hexamethyldisilazane or bistri-methylsilylurea are silylating agents that can be used in the processes of the present invention. The bistri-methylsilyltrihaloacetamide silylating agent can have any halo group as a moiety thereof, such as chloro, fluoro, bromo or iodo. The preferred silylating agent is bistri-methylsilyltrifluoroacetamide (~STFA).
Primarily, the readily available 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ~ and 3,4,5,6-tetra-chloro-1,2-benzoquinone are preferred for use in the .~

.. . ~ .

y: ~ :

1331~1 0236/CMCl - 10 - 17474Y

process of the present invention, but any other quinone of sufficient reaction potential can also be used. Por example, ortho- or para-benzoquinones of the following formula:

o o R~ R 4 R~ ~o Rl 4 ~R14 R14 R14 where R14 is hydrogen, Cl_6 alkyl, Cl_6 alkoxy, halo such as Cl, F, I, Br, nitro or cyano, can be used in the present invention. This would include quinones such as 2,3,5-trimethyl-1,4-benzoquinone, 2,6-dimethyl-1,4-benzoquinone, 2,6-di-t-butyl-1, 4-benzoquinone, 3,5-di-t-butyl-1,2-benzoquinone and 2,3-di-alkoxy-1,4-benzo-quinone. Other quinones of sufficient reaction potential can be substituted for DDQ and still be within the scope of the present invention.
As a general procedure, a lactam, lactone or 3-keto-4-azasteroid is treated with a quinone and a silyating agent in aliphatic or cyclic ethers, or chlorinated or aromatic hydrocarbon solven~s with or ~ . .

t)236/CMCl - 11 - 17474Y

without strong acid catalysis and with or without preliminary low temperature aging and then, first at a lower temperature, and then at elevated tempera-tures under nitrogen for 5 to 25 hours to cleanly produce the corresponding dehydrogenated lactam, or lactone in high yield. These conditions were also used to convert a 3-keto-4-azasteroid to the cor-responding~91-azasteroid with consistently high yields.
The reaction scheme can be represented as follows, in which R4 is methyl for the case in which the silylating agent is BSTFA:

Z o ~ Cl )~/CN

(\~ ~ Cl~CN ~ Cl:~C-NS1~33 ~ :

B~

Cl z 25~R~)3s~o Sol ver~t 30ReElux E~ \X
~ (~) J

~ .. ,~,, ~

~ 3316~

0236/CMCl - 12 - 17474Y

h~ a t ~ ~V

1 0 B~
When X is NRl, O or CH2, the compound of A
is reacted with DDQ and BSTFA to form a diastereomeric intermediate B of the following partial structure, in which R4 is methyl:

Cl Cl~f C R4 ) 3 S iO /~CH he a t CN C :
O / X / :,:
~!5 !

-l33l6al 0236/CMCl - 13 - 17474Y

OH
CH C1~ CN

~;C \ ~ Cl /~N
OSl~ R4)3 ~_~R, O o, CH~
Heating the diastereomeric mixture B results in formation of the corresponding ~1 compound.
Cyclohexane-1,3-dione is used to decompose the residual DDQ prior to thermolysis.
When X is N or CH2, the compound A is reacted with DDQ and BSTFA to form an intermediate according to the following partial structure, in which R4 is methyl: :

Cl C1~

25 (R4)3S~o/~CH/~ heat I ' CR4~3sio Y

C

13316~1 0236/CMCl - 14 - 17474Y

OH
~7, Cl ~CN

(R4)3Sio/ y~ Cl/~N
OSl~R4)3 Y= N, CH2 For example, the 17~-carboxy-4-aza-androstan-3-one (A) is reacted with dichlorodicyano-p-benzoqui-none (DDQ) and biætrimethyl-silyltrifluoro-acetamide ~BSTFA) to form a diastereomeric intermediate (B).
The intermediate (B) i8 subjected to dioxane reflux under heat to form the 17~-carboxy-3-oxo-4-substi-tuted-4-aza-androst-1-ene-3 one (C) corresponding to 20 formula I. -The novel chemical intermediates formed in -the process disclosed herein is also a significant part of the present invention. These novel chemical intermediates (B) are formed as diastereomeric mixtures, however, each diastereomer is included within the scope of the invention. The intermediates :.-are compounds of the formula:

.

:
-~ ',.'',`i ,. ...`.

133~601 0236/CMCl - 15 - 17474Y

S ~~

R"

( I) wherein:
Q is absent or is i~ R l ~O

20~R4)3sio~Rl 4 or Rl 4~or or Rl 4 --OH
-OH

where R is Cl 8 straight or branched chain alkyl, for example, methyl,! C3 6 cycloalkyl, phenyl or combinations thereof; and R is hydrogen, Cl 6 straight or branched alkyl, Cl 6 alkoxy, halo, nitro or cyano;

.30 ' 1331 ~01 0236/CMCl - 16 - 17474Y

is (a) when Q is present, o/~x/ ,, where X is NRl, O or CH2; and Rl is absent or is hydrogen, methyl or ethyl; :~-(b) :

( R~)3 SiO X' where X' is N or CH;

(c) ' -~ ' ~ ~ -11 ~-( R~) 3 S10 X-5 whe~e X" is O or CH2;
z is (1) B-hydrogen and a-hydroxyl, (2) a-hydrogen or a-hydroxyl and :

.

1331~0~

023~/CMCl - 17 - 17474Y

(a) -Alk-C-R8, where Alk is present or absent and i8 a straight or branched hydrocarbon chain of 1 to 12 carbon atoms; and R8 is, (i) hydrogen, (ii) hydroxyl, (iii) C1_12 alkyl (iv) NR9R10, where R9 and R10 are each independently selected from hydrogen;
C1_12 straight or branched chain alkyl;
C1_12 straight or branched chain alkyl having a hydrogen substituted with a hydroxy, carboxylic acid or Cl_4 alkyl ester; C3-6 cycloalkyl; phenyl; or R9 and R10 taken together with the nitrogen to which they are attached represent a 5-6 membered saturated ring comprising up to one other heteroatom selected from oxygen and nitrogen; or (v) ORll, where Rll is M, where M is hydrogen or alkali metal, or Cl_lg strailght or branched chain alkyl;
benzyl; or ~b) -(Alk)-OR12, where Alk is always present and ~ :
has the same meaning as above; and -` :

1331~1 0236/CMCl - 18 - 17474Y

R12 iS
(i? phenyl Cl_6 alkylcarbonyl, ~ii) C5_10 cycloalkylcarbonyl, (iii) benzoyl, or (iv) Cl_lg alkoxycarbonyl;
(v) amino, or Cl_g alkyl sub~tituted amino, :
carbonyl; or (vi) hydrogen, provided that Alk is a branched C3-C8 chain; ~ -10 (3) IOI
=CH-Alk-C-R8 ~:

or-CH-Alk-OR12, where Alk is present or absent and has the same meaning as above, and R8 and R12 have the same meaning as above, and R12 is also hydrogen or C1_20 alkylcarbonyl;

(4) - ~:

' I I
\"

where the dashçd bond replaces the 17a hydrogen; !

: ~ O ' (5) a-hydrogen and NHC-R13, ~.

133~01 0236/CMCl - 19 - 17474Y

where R13 is, (a) Cl_l2 alkyl; or (b) NR9R10;

(6) a-hydrogen and cyano; or (7) a-hydrogen and tetrazolyl;
R' is hydrogen or methyl;
R" is hydrogen or B-methyl;
R"' is hydrogen, B-methyl or hydroxyl.

The following examples should be considered as not limiting the invention and will serve to illustrate the manner in which the present invention iæ accomplished.

E~UMPLEi_l 3-Oxo-4-,aza-Sa-andro6t-l-ene-17~-carboxYlic acid A 1 1 three neck round bottom flask equipped with a nitrogen inlet, reflux condenser, addition funnel, mechanical stirrer and an immersion ~ ' thermometer was charged with 180 mL dioxane followed by 18 g of 3-oxo-4-aza-5a-androstan-17B-carboxylic ~-acid portionwise with stirring. To the stirred suspension was,a~d,deld po,rtionwise 13.86 g of DDQ. The flask was e~acuated (22" Hg) and flushed with nitrogen ~; three times. To this stirred suspension was added BSTP'A via the addition funnel at the rate of 50 mL/minute. The temperature slowly went up form 22 to 25 in a period of thirty minutes as most of the solids dissolved within this period to afford a clear solution.

r~

1331~1 0236/CMCl - 20 - 17474Y

The æolution waæ ætirred for 18 houræ at 22 after wh~ch time formation of the two diasterQomeric adduct6 were observed.
To the solution was added 0.54 g cyclohexane-1,3-dione and the reaction mixture was stirred at 22 for an additional three hours to decompose any residual DDQ, The solution was then heated in an oil bath so that a very gentle reflux was maintained.
(Bath temperature 120, Internal Temperature 108) After refluxing for 20 hours complete disappearance of the adducts and formation of wl acid were observed.
The reaction mixture was cooled to 22 and poured slowly over a period of 2 minutes into a stirred mixture of 300 mL CH2C12 and 60 mL 1% aqueous sodium bisulfite solution.
The flask was rinsed with 50 mL CH2C12.
After the mixture was stirred for thirty minutes, 18 mL 6N HCl was added to this mixture and stirred for 2 an additional thirty minutes. The heterogeneous mixture was filtered and the residue was washed with 60 mL lN HCl followed by 250 mL CH2C12. The filtrated was transferred into a seperatory funnel and allowed to settle. The bottom CH2C12 layer containing the product was separated from the top aqueous layer and the top layer was washed,with 60 mL
CH2C12. The combined CH2C12 layer was washed with 200 mL 2N HCl. The aqueous layer was washed with 60 mL CH2C12. The two CH2C12 solutions were combined.
The liquid chromatography yield at this stage was 16.0 g (88%). The combined CH2C12 solution was then distilled and concentrated to about 120 mL volume.
The dis~illation waæ continued and acetonitrile was added to the flask at such a rate 80 that ~he total 1331~1 0236/CMCl - 21 - 17474Y

volume was maintained at approximately 120 mL. After addition of about 400 mL acetonitrile the diætillation head showed a temperature of about B2.
Gaæ chromatography analysiæ performed on the mother liquor showed the presence of about 2% dioxane. The distillation was discontinued at this point. The suspension was cooled to 20 and aged at 20 for 20 hours with stirring. The crystals were filtered and washed with acetonitrile until the filtrate was colorless. Approximately 100 mL acetonitrile was used for the wash. The wet cake was dried at 60C
under vacuum (about lmm mg) overnight to produce 15.3 g of the wl acid.

17B-(t-butylcarbamoyl)-4-aza-5a-androst-1-ene-3-one A 50 ml three neck round bottom flask equipped with a nitrogen inlet, reflux condenser, addition funnel, magnetic stirrer and an immersion thermometer was charged with 10 ml dioxane followed by 1 g of 17B-N-(t-butylcarbamoyl)-4-aza-5a-androstan-3-one portionwise with stirring. To the stirred suspension was added portionwise 0.656g DDQ.
The flask was evacuated (20" Hg) and flushed with nitrogen three times. To this stirred suspension was added BSTFA via a syringe at the rate of about 2 mL/min. Most of the solids dissolved during a period of half of an hour to afford a clear red solution. `
The solution was stirred for 18 hours at 22 after which time complete diæappearance of stahding material and formation of the two diastereometric 1 3 ~
0236/CMCl - 22 - 17474Y

adducts were observed by liquid chromatography. To this solution was added cyclohexane-1,3-dione and the reaction mixture was stirred at 22 for an add~tional three hours to decompose any residual DDQ. The solution was then heated in an oil bath so that a very gentle reflux was maintained. After refluxing for 20 hours complete disappearance of the adducts and formation of the title compound were observed by liquid chromatography. The reaction mixture was 1 cooled to 22 and poured slowly into a stirred mixture of 30 ml CH2~12 and 6 mL 1% aqueous sodium bisulfite solution. The flask was rinsed with 10 mL
CH2C12. After the mixture was stirred for 15 minutes 4 mL 6N HCl was added to this mixture and stirred for an additional 15 minutes. The hetero-geneous mixture was filtered and the residue was washed with 20 mL CH2C12. The filtrate was transferred to a seperatory funnel and allowed to settle. The bottom CH~C12 layer containing the product was separated from the top aqueous layer and the top layer was washed with 20 mL CH2C12. The combined CH2C12 layer was washed with 20 mL 2% sodium hydroxide solution. The CH2C12 solution was then distilied and concentrated to about 6 mL volume. The distillation was continued and isopropyl acetate was added ~o the flask at such a rate so that the total volume was maintained at approximately 6 mL. The distillation was discontinued when the distillation head showed a temperature of about 85. The suspension was cooled at 0 for 6 hours. The crytals were filtered and waæhed with 2 mL isopropyl ; , . , , . - . , .. : , 0236/CMCl - 23 - 17474Y

acetate. The crystal6 were dried at 60 under vacuum (1 mr Hg) overnight to produce 0.8 g of the title compound (80%).

To 250 mg of 17-~-(t-butylcarbamoyl)-4-aza-5a-androstan-3-one in a glass NMR tube were added approximately 2 mL of methylene chloride (as a CH2C12CD2C12 mixture suitable for NMR studies), 0.7 mL BSTFA and 60 mcL CF3S03H. The tube was cooled in methanol-ice and 168 mg tetrachloro-1,2-benzoquinone added accompanied by injection of a stream of dry 2 N2. The tube was then closed with a snugly fitting polyethylene stopper, sealed with stretched ParafilmR, agitated briefly with only momentary warming, and placed in a cooled NMR probe which had been previously adjusted for 13C observations of reaction intermediates at approximately-5C. Spectra 20 were obtained from time to time over a period of two -~
days during which the sample temperature was maintained between zero and -10C. The solution was then allowed to age five days at ambient temperature while additional sepct~a were recorded from time to time. At the end of this aging the entire solution was quantitatively transferred, quenched with 1 mL
acetic acid and volumetrically diluted for replicate HPLC analyses which gave 80-84% yield, based on assay vs pure 17-B-(t-butylcarbamoyl)-4-aza-5a-androst-1-ene-3-one, from the saturated lactam precursor.

1331~01 0236/CMCl - 24 - 17474Y

A 100 mL three-neck round bottom flask equipped with a nltrogen inlet, reflux condenser, magnetic stirrer and a septum inlet was charged with 17-B-(t-butyl-carbamoyl)-4-aza-Sa-androstan-3-one (4.0 g), DDQ (4.0 g) and dioxane (26 ml). To this suspension was added BSTFA (10.5 g) with stirring via a syringe over a period of 1 min. Heating the mixture at reflux for 10 minutes afforded a clear solution. The solution was refluxed for 18 hours at the end of which complete disappearance of starting material was observed by LC. The solution was cooled to room temperature and added to a mixture of 100 mL each 5% NaHS03 and CH2C12, precipitating the hydroquinone which was separated by filtration. The CH2C12 layer of the filtrate was separated, extracted twice with 100 mL
of 5% NaHSO3, concentrated to a thick oil and triturated with 200 mL diethyl ether. First and second crop solids were isolated and dried 4 hours at 50 under vacuum yielding a total of 3.28 g of 88%
pure 17-B-(t-butylcarbamoyl)-4-aza-Sa-androst-l-ene-3-one.

3-Oxo-4-aza-5a-androst-1-ene-17B-carboxylic acid (~-Aza acid) A 1 L 3-neck round bottom flask equipped with a nitrogen inlet, reflux condenser, additional funnel, mechanical stirrer and an immersion thermometer w~s charged with 320 mL of toluene, 20 g 1.331 601 1~236/CMCl - 25 - 17474Y

of 3-oxo-4-aza-Sa-androstan-17B-carboxylic acid, 15.7 g of DDQ, 70 mL of ~STFA and 0.32 mL of triflic acid. The flask was evacuatQd and flushed with N2 three times. The reaction mixture was stirred for 18 h at 3~-40 after which time complete disappearance of starting material and formation of two diastereo-meric adducts was observed by LC. Cyclohexane-1.3-dione (0.8 g) was added and the reaction mixture was stirred at 38-40 for 3 hours to quench any residual DDQ. The solution was then heated to gentle reflux for 20 h after which time complete disappearance of the adducts and formation of the Wl-acid (95% assay yield) was observed by LC. The reaction was cooled to 20C. Aqueous NaOH (430 mL, 1% by wt) and 120 mL
of isopropanol were added. The mixture was stirred for 30 min, allowed to settle and the bottom aqueous layer was re-extracted with a mixture of 430 mL
toluene and 120 mL i-propanol. The combined toluene layers were extracted with 320 mL of 1% NaOH. The bottom aqueous layer containing the product was extracted and the organic layer was washed with another 160 mL of 1% NaOH. The aqueous layers were combined and isopropanol removed by vacuum distillation and replaced with 100 mL of acetonitrile.
25~ The mixture was warmed to 60-65C and acidified with 12 mL of 6N HCl to pH 1, aged at 60-65C for 2 hours, cooled to 20C and aged for 18 hours and filtered.
The filter cake was washed with 100 mL of H20~ ~H3CN
(4/1). The product was dried at 50-60C under vacuum to yield 17.6 g (88%) of the desired Wl-aza acid.

133~6~1 0236JCMCl - 26 - 17474Y

Methyl-3-oxo-4-aza-5a-androst-1-ene-17~-carboxylate A 1 L three-neck round bottom flask equipped S with a nitrogen inlet, reflux condenser, additional funnel, mechanical stirrer and an immersion thermometer was charged with 320 mL of toluene, 20 g of methyl-3-oxo-4-aza-Sa-androstan-17~-carboxylate, 14.73 g of DDQ, 67 mL of BSTFA and 0.32 mL triflic acid. The flask was evacuated and flushed with N2 three times. The reaction mixture was stirred for 18 h at 22 after which time complete disappearance of starting material and formation of the two diastereo-meric adducts was observed by LC. Cyclohexane-1,3-dione was added and the reaction mixture was stirredat 22 for 3 hours to quench any residual DDQ. The solution was then heated to gentle reflux for 20 h after which time complete disappearance of the adducts and formation of the methyl-3-oxo-4-aza-5-androst-1-ene-17-carboxylate was observed by LC. The toluene solution was cooled to 22C and 42 mL CH2C12 and 390 mL ~aturated sodium bicarbonate solution added with stirring. The bottom layer was separated from the top organic layer containing the product.
The top layer was washed once more with 390 mL
saturated sodium bicarbonate solution. The toluene solution was distilled to 100 mL volume. Toluene was displaced by n-Butylacetate via distillation maintaining 100 mL volume. The slurry was aged at 22 for 18 hours and fil~ered to produce the product steroid in 91~ yield.

133~

0236/CMCl - 27 - 17474Y

E~AMPLE 7 By following the procedure of the preceding example a 90% yield of 17B-tt-butylcarbamoyl)-4-aza-5a-androst-1- ne-3-one was obtained from the corresponding 17B-(t-butylcarbamayl)-4-aza-5-a-androstan-3-one.

1~ By following the procedure of the preceeding example a 90% yield of 22(R,S)-methyl-4-aza-21-nor-5a-cholen-3,20-dione was obtained from the corresponding 22tR,S)-methyl-4-aza-21-nor-5a-cholan-3,20-dione.

A 100 mL three neck round bottom flask eguipped for magnetic stirring and a nitrogen inlet was charged with 2 g of 17B-(t-butylcarbamoyl)-4-` 20 aza-5a-androstan-3-one, 20 mL CH2C12, and 1.344 g of ~ ~-ortho-chloranil. The solution was cooled to -8 by means of methanol/ice cooling and 6 mL BSTFA was added via syringe (ca. 1 min) followed by 0.48 mL
triflic acid. The solution was stirred at -10 for 2 days~followed by 22 for 6,days, after which time complete disappearance of starting material was observed by LC. At the end of thi~ age HPLC analyses showed 1.6 g of 17B-(t-butylcarbamoyl)-4-aza-5a-androst-1-ene-3-one (based on assay vs pure 17B-tt-butylcarbamoyl)-4-aza-5a-androst-1 ene-3-one; yield 80%.

1 3 ~

0236/CMCl - 28 - 17474Y

rsolation of the diastereomeric adduct formed between 3-oxo-4-aza-Sa-androstan-17B-carboxYlic acid and DDQ
A 100 mL 3 nec'c round bottom flask equipped with a nitrogen inlet a~ld magnetic stirring was charged with 20 mL tetrahydropyran, 2g of 3-oxo-4-aza-5a-androstan-17B-carboxylic acid, 6.7 mL of BSTFA, 1.47 g of DDQ and 2 mcL of triflic acid. The solution was stirrd under N2 for 20 hours at 22 after which time complete disappearance of starting material and formation of the two diastereomeric adducts was observed by LC. The solution was cooled to 4 ~ice cooling) and 0.2 mL water was added to it. The mixture was stirred at 4 for 3 hours. The solvent was removed at 20 in the rotovapor to afford a yellow oil which was tritiated with 60 mL CH2C12.
The two diastereomeric adduct crystallized. The crystals were aged for 1 hour at 22 filtered, washed with 20 mL CH2C12 and dried in vacuum at 22 to afford 90% yield of the two diastereomeric adducts.

Preparation of 3-oxo-4-aza-5a-androst-1-ene-17~-carboxylic acid via thermolysis of the isolated S diasteremeric adducts .
loO mg of the two diasteromeric adducts (obtained in Example 10) were heated in 2 mL dioxane under N2 atmosphere for 18 hours to produce 36 mg (by LC analysis, 60%) of the desired 3-oxo-4-aza-Sa-3 androst-1-ene-17~-carboxylic acid. -; .
:

1331~01 0236/CMCl - 29 - 17474Y

By following the procedures of Example 1 or 2 but substituting the corresponding 1,2-saturated steroid as a starting material, the ollowing compounds could be obtained.

Compound Example Name 12 17~-hydroxy-4-aza-5a-androst-1-en-3-one 13 3-oxo-4-aza-5a-preg-l-ene-20a-carboxylic acid 14 methyl-3-oxo-4-aza-5a-pregn-l-ene-20a-car-boxylate 2',3'a-tetrahydro-furan-2'-spiro-17-(4-aza-5a-androst-1-en-3-one) 16 23-methyl-4-aza-21-nor-5a-chol-1-ene-3,20-dione 17 17B-(2-pyrrylcarbonyl)-4 -aza-5a-androst-1-en-3-one 133~9~

0236/CMCl - 30 - 17474Y

Compound Exam~le Name 18 17B-(t-but.yldimethyl-silyloxy)-4-aza-5a-androst-l-en-3-one 19 3-oxo-4-aza-5a-androst-l-ene-17~-carboxamide N-ethyl-3-oxo-4-aza-5a-androst-1-ene-17B-carboxamide 21 N-~2,4,4,-trimethyl-2-pentyl) 3-oxo-4-aza-5a-androst-1-ene-17B-carboxamide 22 N,N-bis(2-propyl) 3-oxo-4-aza-5a- ~
androst-l-ene-17B- :
carboxamide ..
23 17B-hydroxy-4-methyl-4-aza-5a-androst-1-en-3-one 24 4-methyl-3-oxo-4-aza-5a-pregn-1-ene-20a-carboxylic acid 13~16~1 0236/CMCl - 31 - 17474Y

Compound Example Name methyl 4-methyl-3-~o-4-aza-5a-pregn-1-20a-carboxylate 26 2',3'a-tetrahydro-furan-2'-spiro-17-(4-methyl-4-aza-5a-androst-l-en-3-one) 27 4,23-dimethyl-4-aza-21-nor-5a-chol-1-ene-3, zo-dione 28 4,22-dimethyl-4-aza-21-nor-5a-chol-1-ene-3,20-dione 29 4-methyl-17~-(2-pyrryl-carbonyl)-4-aza-Sa-androst-l-en-3-one , j ~ ~ 17B-(t-butyldimethyl- -silyloxy)-4-methyl-4-aza-5a-androst-1-en-3-one 31 methyl 4-methyl-3-oxo-4-aza-5a-androst-1-ene-17~-carboxylate 133~01 0236/CMCl - 32 - 17474Y

Compound Example Name 32 4-methyl-3-oxo-4-aza-Sa-androst-l-ene-17n-carboxamide 33 N-ethyl 4-methyl-3-oxo-4-aza-5a-androst-l-ene-17~carboxamide 34 N-(t-butyl) 4-methyl-3-oxo-4-aza-5a-androst-l-ene-17~-carboxamide :

N-octyl 4-methyl-3-oxo-4-aza-5a-androst-l-ene-17B-carboxamide 36 N-(2,4,4-trimethyl-2-pentyl) 4-methyl-3-: oxo-4-aza-5a-androst-l-ene-17B-carboxamide 37 , ~ I N,N-bis(2-propy~) 4-methyl-3-oxo-4-aza-5a-androst-l-ene-17~-carboxamide

Claims (23)

1. A process for dehydrogenating a compound of the formula (I) (II) (III) where Formula (I) may alternatively have the structure of partial Formulas (II) and/or (III);
wherein, A is (1) -CH2-CH2-;

(2) B is (1) where X is N,O or CH2; and R1 is absent or is (a) hydrogen;
(b) methyl or ethyl;
(c) NR2R3 where R2 and R3 are hydrogen or methyl; or (d) cyano; or (2) (a) (b) (c) (d) (e) where R4 is C1-8 straight or branched chain alkyl, C3-6 cycloalkyl, phenyl, or combinations thereof;

R' is hydrogen or methyl;
R" is hydrogen or .beta.-methyl;
R"' is hydrogen, .beta.-methyl or hydroxyl;

z is (1) .beta.-hydrogen and a-hydroxyl;
(2) a-hydrogen or a-hydroxyl and (a) where Alk is present or absent and is a straight or branched hydrocarbon chain of 1 to 12 carbon atoms; and R8 is, (i) hydrogen, (ii) hydroxyl, (iii) C1 12 alkyl, (iv) NR9R10, where R9 and R10 are each independently selected from hydrogen;
C1-12 straight or branched chain alkyl, C1-12 straight or branched chain alkyl having a hydrogen substituted with a hydroxy, carboxylic acid or C1-4 alkyl ester; C3-6 cycloalkyl; phenyl; or R9 and R10 taken together with the nitrogen to which they are attached represent a 5-6 membered saturated ring comprising up to one other heteroatom selected from oxygen and nitrogen; or (v) OR11, where R11 is M, where M is hydrogen or alkali metal, or C1-18 straight or branched chain alkyl;
benzyl: or (b) -(Alk)-OR12, where Alk is always present and has the same meaning as above; and R12 is (i) phenyl C1-6 alkylcarbonyl, (ii) C5-10 cycloalkylcarbonyl, (iii) benzoyl, or (iv) C1-18 alkoxycarbonyl;
(v) amino, or C1-8 alkyl substituted amino, carbonyl; or (vi) hydrogen, provided that Alk is a branched C3-C8 chain;

(3) =CH-Alk-?-R8 or=CH-Alk-OR12, where Alk is present or absent and has the same meaning as above, and R8 and R12 have the same meaning as above, and R12 is also hydrogen or C1-20 alkylcarbonyl;

(4) where the dashed bond replaces the 17a hydrogen;

(5) a-hydrogen and NH?-R13, where R13 is, (a) C1-12 alkyl; or (b) NR9R10;

(6) a-hydrogen and cyano; or (7) a-hydrogen and tetrazolyl;
which comprises reacting the compound with a silylating agent in the presence of a quinone to introduce a .DELTA.1 double bond.

2. A process according to Claim 1 wherein the silylating agent is a bistrimethylsilyltrihalo-acetamide, bistrimethylsilylacetamide, hexamethyl-disilazane, or bistrimethylsilylurea.

3. A process according to Claim 2 wherein the quinone is:

where R14 is hydrogen, C1-6 alkyl, C1-6 alkoxy, halo, nitro or cyano.

4. The process according to Claim 3 wherein the quinone is 2,3-dichloro-5,6-dicyano-1,4-benzoquinone.

5. A process according to Claim 1 wherein A is -CH2-CH2-;

B is where R1 is (a) hydrogen:
(b) methyl or ethyl;
R", R"' are hydrogen; and Z is -?-R8 where R8 is (i) -NHC3-12 branched alkyl;
(ii) -NHC3-12 branched alkyl having a hydrogen substituted with a hydroxy, carboxylic acid or C1-4 alkyl ester;
(iii) -C3-12 branched alkyl; or (iv) -OCH3.

6. A process according to Claim 5 wherein the silylating agent is a bistrimethylsilyltrihalo-acetamide, bistrimethylsilylacetamide, hexamethyl-disilazane, or bistrimethylsilylurea.

7. A process according to Claim 6 wherein the silylating agent is bistrimethylsilyltrifluoro-acetamide and the quinone is 2,3-dichloro-5,6-dicyano-1,4-benzoquinone.

8. A process according to Claim 7 wherein R1 is hydrogen and R8 is -NH-t-butyl.

9. A dehydrogenation process which com-prises reacting 17.beta.-N-(t-butylcarbamoyl)-4-aza-5a-androstan-3-one with a silylating agent in the presence of a quinone to form 17.beta.-N-(t-butylcar-bamoyl)-4-aza-5a-androst-1-en-3-one.

10. A process according to Claim 9 wherein the silylating agent is bistrimethylsilyltrifluoro-acetamide and the quinone is 2,3-dichloro-5,6-dicyano-1,4-benzoquinone.

11. A process according to Claim 1 which comprises reacting 23-methyl-4-aza-21-nor-5a-cholan-3,20-dione with a silylating agent in the presence of a quinone to form the .DELTA.1 compound.

12. A process according to Claim 1 which comprises reacting 22-methyl-4-aza-21-nor-5a-cholan-3,20-dione with a silylating agent in the presence of a quinone to form the .DELTA.1 compound.

13. A process according to Claim 1 which comprises reacting 3-oxo-4-aza-5a-androstan-17.beta.-carboxylic acid dione with a silylating agent in the presence of a quinone to form the .DELTA.1 compound.

14. A process according to Claim 1 which comprises reacting 17.beta.-(isopropylcarbonyl)-4-aza-5a androstan-3-one with a silylating agent in the presence of a quinone to form the .DELTA.1 compound.

15. A process according to Claim 1 which comprises reacting 17.beta.-(carbomethoxy)-4-aza-5a-androstan-3-one with a silylating agent in the pre-sence of a quinone to form the .DELTA.1 compound.

16. A Compound of the formula - (I) wherein:

Q is absent or is or or or -OH
-OH

where R4 is C1-8 straight or branched chain alkyl, C3-6 cycloalkyl, phenyl, or combinations thereof; and R14 is hydrogen, C1-6 alkyl, C1-6 straight or branched chain alkoxy, halo, nitro or cyano:

B is (a) when Q is present, where X is NR1, O or CH2; and R1 is absent or is hydrogen, methyl or ethyl;

(b) where X' is N or CH;

(c) where X" is O or CH2;
Z ii (1) .beta.-hydrogen and a-hydroxyl;
(2) a-hydrogen or a-hydroxyl and (a) -Alk-?-R8, where Alk is present or absent and is a straight or branched hydrocarbon chain of 1 to 12 carbon atoms; and R8 is, (i) hydrogen, (ii) hydroxyl, (iii) C1-12 alkyl (iv) NR9R10, where R9 and R10 are each independently selected from hydrogen;
C1-12 straight or branched chain alkyl;

C1-12 straight or branched chain alkyl having a hydrogen substituted with a hydroxy, carboxylic acid or C1-4 alkyl ester; C3-6 cycloalkyl; phenyl; or R9 and R10 taken together with the nitrogen to which they are attached represent a 5-6 membered saturated ring comprising up to one other heteroatom selected from oxygen and nitrogen; or (v) OR11, where R11 is M, where M is hydrogen or alkali metal, or C1-18 straight or branched chain alkyl;
benzyl; or (b) -(Alk)-OR12, where Alk is always present and has the same meaning as above; and R12 is (i) phenyl C1-6 alkylcarbonyl, (ii) C5-10 cycloalkylcarbonyl, (iii) benzoyl, or (iv) C1-18 alkoxycarbonyl;
(v) amino, or C1-8 alkyl substituted amino, carbonyl; or (vi) hydrogen, provided that Alk is a branched C3-C8 chain;
(3) =CH-Alk-?-R8 or = CH-Alk-OR12, where Alk is present or absent and has the same meaning as above, and R8 and R12 have the same meaning as above, and R12 is also hydrogen or C1-20 alkylcarbonyl;

(4) where the dashed bond replaces the 17a hydrogen;

(5) a-hydrogen and NH?-R13, where R13 is, (a) C1-12 alkyl; or (b) NR9R10;

(6) a-hydrogen and cyano; or (7) a-hydrogen and tetrazolyl;
R' is hydrogen or methyl;
R" is hydrogen or .beta.-methyl;
R"' is hydrogen, .beta.-methyl or hydroxyl.

17. A compound of claim 16, wherein Q is present and R4 is methyl;

.beta. is where X is NR1:

R", R"' are hydrogen;

Z is -?-R8 where R8 is (i) -NHC3-12 branched alkyl;
(ii) -NHC3-12 branched alkyl having a hydrogen substituted with a hydroxy, carboxylic acid or C1-4 alkyl ester;

(iii) -C3-12 branched alkyl; or (iv) -OCH3.

18. A compound of claim 17, wherein R8 is -NH-t-butyl, , sec-butyl, isobutyl or -OCH3.

19. The compound of Claim 18 wherein R1 is hydrogen and R8 is -NH-t-butyl.

20. The compound of Claim 19 where Q is or -OH

21. The compound of Claim 19 where Q is or -OH

22. A process according to claim 1 or 5, wherein R4 is methyl.

23. A compound of claim 16, wherein R4 is methyl.

CA000570228A 1987-06-29 1988-06-23 Dehydrogenation process Expired - Lifetime CA1331601C (en)

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