16-Dehydropregnenolone acetate

16-Dehydropregnenolone acetate
Names
	IUPAC name 20-Oxopregna-5,16-dien-3β-yl acetate
	Systematic IUPAC name (3aS,3bR,7S,9aR,9bS,11aS)-1-Acetyl-9a,11a-dimethyl-3a,3b,4,6,7,8,9,9a,9b,10,11,11a-dodecahydro-3H-cyclopenta[a]phenanthren-7-yl acetate
	Other names 16-DPA; 5,16-Pregnadien-3β-ol-20-one acetate; 3β-Hydroxy-5,16-pregnadien-20-one acetate; 3β-Acetoxy-5,16-pregnadien-20-one
Identifiers
CAS Number	979-02-2;
ChEBI	CHEBI:34163;
ChEMBL	ChEMBL1761683;
ChemSpider	83823;
ECHA InfoCard	100.012.326
EC Number	213-558-7;
KEGG	C14503;
PubChem CID	92855;
UNII	832VMW7ZGC ;
CompTox Dashboard (EPA)	DTXSID8057857 ;
	InChI InChI=1S/C23H32O3/c1-14(24)19-7-8-20-18-6-5-16-13-17(26-15(2)25)9-11-22(16,3)21(18)10-12-23(19,20)4/h5,7,17-18,20-21H,6,8-13H2,1-4H3/t17-,18-,20-,21-,22-,23+/m0/s1 Key: MZWRIOUCMXPLKV-VMNVZBNLSA-N;
Properties
Chemical formula	C23H32O3
Molar mass	356.506 g·mol−1
Appearance	White crystalline powder
Melting point	171–172 °C (340–342 °F; 444–445 K)
	Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa). Infobox references

16-Dehydropregnenolone acetate (16-DPA) is a chemical compound used as an intermediate or synthon in the production of many semisynthetic steroids. While it is not easy to synthesize, it is a convenient intermediate which can be made from other more available materials, and which can then be modified to produce the desired target compound.

Upstream sources

16-DPA can be produced from a variety of steroidal sapogenins. Industrially useful sources are diosgenin in Mexican yams and solasodine from certain nightshades. These two sapogenins can be used in a one-pot synthesis. Solanidine in potato greens, an alkaloid sapogenin, is also a key source material.

Downstream products

Compounds derived from 16-DPA include:

Corticosteroids (mainly of a C22 pregnane backbone): hydrocortisone*, betamethasone*, dexamethasone*, beclometasone*, fluticasone, and prednicarbate;
Progestogen (mainly of a C22 pregnane backbone): pregnenolone, progesterone*, various synthetic derivatives such as medroxyprogesterone acetate* and levonorgestrel*;
Androgens (mainly of a C19 androstane, 17-keto backbone): testosterone* and esters, various synthetic derivatives;
Estrogens (mainly of a C18 estrane, 17-hydroxy backbone): estradiol and esters such as estradiol cypionate*, various synthetic derivatives such as ethinylestradiol*.
Guggulsterone
DHEA
Pregnenolone 16α-carbonitrile
Mecigestone

Those marked with a * appear on the WHO Model List of Essential Medicines, some as part of a compound medication. The list is by no means complete due to the central role of 16-DPA in steroid production.

Pharmacology

There are no current medical uses of 16-DPA. Studies in male hamsters show that the related chemical 16-DHP acts as an farnesoid X receptor (FXR) antagonist, consequently up-regulating CYP7A1 and lowering serum cholesterol. The CSIR-CDRI holds a patent over 16-DHP for prospective lipid-lowering use.

History

Production of substantial quantities of steroids was not achieved until the Marker degradation in the late 1930s, a synthesis route converting diosgenin into the related compound 16-dehydropregnenolone (16-DP or 16-DHP). This reaction established Mexico as a world center of steroid production. 16-DPA was produced in a variant of Marker degradation published in 1940.

The earliest PubChem patent record for 16-DPA is US2656364A of 1951, describing its conversion into 17-ketosteroids.

Synthesis

Lednicer covers the synthesis of 16-DPA in his book of steroids. It is produced by the Marker degradation of diosgenin (which itself is a product from the hydrolysis of glycoside saponin called dioscin). There is a large bevy of 16-DPA syntheses reported in the literature and patents (too many to record here). Notable ones that are creditworthy of mention include a one-pot synthesis and a green method.

Also worth mentioning is that in addition to the Marker degradation of diosgenin, it is also possible to make 16-DPA from Solasodine and Solanidine (q.v.). These derived from nightshade alkaloids and not Mexican yams.

References

↑ us 5808117, Pritish Kumar Chowdhury, "Process for the production of 16-Dehydropregenolone acetate form diosgenin", issued 15-09-1998
↑ Baruah, Diganta; Das, Ram Nath; Konwar, Dilip (2015). "Facile green synthesis of 16-dehydropregnenolone acetate (16-DPA) from diosgenin". Synthetic Communications. 46 (1): 79–84. doi:10.1080/00397911.2015.1121280. S2CID 98360074.
↑ Goswami, Amrit; Kotoky, Rumi; Rastogi, Romesh C.; Ghosh, Anil C. (1 May 2003). "A One-Pot Efficient Process for 16-Dehydropregnenolone Acetate" (PDF). Organic Process Research & Development. 7 (3): 306–308. doi:10.1021/op0200625.
↑ Vronen, Patrick J.E.; Koval, Nadeshda; de Groot, Aede (2003). "The synthesis of 16-dehydropregnenolone acetate (DPA) from potato glycoalkaloids". Arkivoc. 2004 (2): 24–50. doi:10.3998/ark.5550190.0005.203. hdl:2027/spo.5550190.0005.203.
↑ "13.4.7 The Crystal Structure of Dehydropregnolone Acetate: A Pregnane". Chemistry and Pharmacology of Naturally Occurring Bioactive Compounds. CRC Press. p. 308.
1 2 Marker RE, Krueger J (1940). "Sterols. CXII. Sapogenins. XLI. The Preparation of Trillin and its Conversion to Progesterone". J. Am. Chem. Soc. 62 (12): 3349–3350. Bibcode:1940JAChS..62.3349M. doi:10.1021/ja01869a023.
1 2 3 Hershberg, Emanuel B.; Oliveto, Eugene P. (20 October 1953). "Process for the manufacture of 17-keto steroids".
↑ Ramakrishna, Rachumallu; Kumar, Durgesh; Bhateria, Manisha; Gaikwad, Anil Nilkanth; Bhatta, Rabi Sankar (1 April 2017). "16-Dehydropregnenolone lowers serum cholesterol by up-regulation of CYP7A1 in hyperlipidemic male hamsters". The Journal of Steroid Biochemistry and Molecular Biology. 168: 110–117. doi:10.1016/j.jsbmb.2017.02.013. PMID 28232149. S2CID 30520080.
↑ "Russell Marker and the Mexican Steroid Hormone Industry". American Chemical Society. Retrieved June 5, 2012.
↑ Lednicer, D. (2011). Steroid chemistry at a glance. Chemistry at a glance (1. publ ed.). Wiley. ISBN 978-0-470-66084-3.
↑ Marker, Russell E.; Krueger, John (1940). "Sterols. CXII. Sapogenins. XLI. The Preparation of Trillin and its Conversion to Progesterone". Journal of the American Chemical Society 62 (12): 3349–3350. doi:10.1021/ja01869a023.
↑ Numazawa, Mitsuteru; Nagaoka, Maaso; Kunitama, Yurie (1986). "Regiospecific deoxygenation of the dihydroxyacetone moiety at C-17 of corticoid steroids with iodotrimethylsilane.". CHEMICAL & PHARMACEUTICAL BULLETIN 34 (9): 3722–3726. doi:10.1248/cpb.34.3722. ISSN 0009-2363.
↑ Goswami, A.; Kotoky, R.; Rastogi, R. C.; Ghosh, A. C. (2003). "A One-Pot Efficient Process for 16-Dehydropregnenolone Acetate". Organic Process Research & Development 7 (3): 306. doi:10.1021/op0200625.
↑ Baruah, Diganta; Das, Ram Nath; Konwar, Dilip (2015). "Facile green synthesis of 16-dehydropregnenolone acetate (16-DPA) from diosgenin". Synthetic Communications. 46(1): 79–84. doi:10.1080/00397911.2015.1121280.

[1] us 5808117, Pritish Kumar Chowdhury, "Process for the production of 16-Dehydropregenolone acetate form diosgenin", issued 15-09-1998

[2] Baruah, Diganta; Das, Ram Nath; Konwar, Dilip (2015). "Facile green synthesis of 16-dehydropregnenolone acetate (16-DPA) from diosgenin". Synthetic Communications. 46 (1): 79–84. doi:10.1080/00397911.2015.1121280. S2CID 98360074.

[3] Goswami, Amrit; Kotoky, Rumi; Rastogi, Romesh C.; Ghosh, Anil C. (1 May 2003). "A One-Pot Efficient Process for 16-Dehydropregnenolone Acetate" (PDF). Organic Process Research & Development. 7 (3): 306–308. doi:10.1021/op0200625.

[4] Vronen, Patrick J.E.; Koval, Nadeshda; de Groot, Aede (2003). "The synthesis of 16-dehydropregnenolone acetate (DPA) from potato glycoalkaloids". Arkivoc. 2004 (2): 24–50. doi:10.3998/ark.5550190.0005.203. hdl:2027/spo.5550190.0005.203.

[5] "13.4.7 The Crystal Structure of Dehydropregnolone Acetate: A Pregnane". Chemistry and Pharmacology of Naturally Occurring Bioactive Compounds. CRC Press. p. 308.

[Marker1940-6] 1 2 Marker RE, Krueger J (1940). "Sterols. CXII. Sapogenins. XLI. The Preparation of Trillin and its Conversion to Progesterone". J. Am. Chem. Soc. 62 (12): 3349–3350. Bibcode:1940JAChS..62.3349M. doi:10.1021/ja01869a023.

[17k-7] 1 2 3 Hershberg, Emanuel B.; Oliveto, Eugene P. (20 October 1953). "Process for the manufacture of 17-keto steroids".

[8] Ramakrishna, Rachumallu; Kumar, Durgesh; Bhateria, Manisha; Gaikwad, Anil Nilkanth; Bhatta, Rabi Sankar (1 April 2017). "16-Dehydropregnenolone lowers serum cholesterol by up-regulation of CYP7A1 in hyperlipidemic male hamsters". The Journal of Steroid Biochemistry and Molecular Biology. 168: 110–117. doi:10.1016/j.jsbmb.2017.02.013. PMID 28232149. S2CID 30520080.

[Marker_Degradation:_Creation_of_the_Mexican_Steroid_Hormone_Industry-9] "Russell Marker and the Mexican Steroid Hormone Industry". American Chemical Society. Retrieved June 5, 2012.

[10] Lednicer, D. (2011). Steroid chemistry at a glance. Chemistry at a glance (1. publ ed.). Wiley. ISBN 978-0-470-66084-3.

[11] Marker, Russell E.; Krueger, John (1940). "Sterols. CXII. Sapogenins. XLI. The Preparation of Trillin and its Conversion to Progesterone". Journal of the American Chemical Society 62 (12): 3349–3350. doi:10.1021/ja01869a023.

[12] Numazawa, Mitsuteru; Nagaoka, Maaso; Kunitama, Yurie (1986). "Regiospecific deoxygenation of the dihydroxyacetone moiety at C-17 of corticoid steroids with iodotrimethylsilane.". CHEMICAL & PHARMACEUTICAL BULLETIN 34 (9): 3722–3726. doi:10.1248/cpb.34.3722. ISSN 0009-2363.

[13] Goswami, A.; Kotoky, R.; Rastogi, R. C.; Ghosh, A. C. (2003). "A One-Pot Efficient Process for 16-Dehydropregnenolone Acetate". Organic Process Research & Development 7 (3): 306. doi:10.1021/op0200625.

[14] Baruah, Diganta; Das, Ram Nath; Konwar, Dilip (2015). "Facile green synthesis of 16-dehydropregnenolone acetate (16-DPA) from diosgenin". Synthetic Communications. 46(1): 79–84. doi:10.1080/00397911.2015.1121280.