630-56-8

Basic information

• Product Name: 17a-Hydroxyprogesterone caproate
• Synonyms: PREGN-4-ENE-3,20-DIONE HEXANOATE;17-((1-oxohexyl)oxy)-pregn-4-ene-20-dione;17-((1-Oxohexyl)oxy)pregn-4-ene-3,20-dione;17a-hydroxyprogesteronehexanoate;17-alpha-Hexanoyloxypregn-4-ene-3,20-dione;17alpha-Hydroxyprogesterone n-caproate;17-alpha-hydroxyprogesteronen-caproate;17-Hydroxypregn-4-ene-3,20-dione caproate
• CAS NO: 630-56-8
• Molecular Formula: C₂₇H₄₀O₄
• Molecular Weight: 428.6
• EINECS: 211-138-8
• Product Categories: Biochemistry;Hydroxyketosteroids;Steroids;Steroid and Hormone;Hormone Drugs
• Mol File: 630-56-8.mol

Chemical Properties

• Melting Point: 119°C
• Boiling Point: 463.43°C (rough estimate)
• Flash Point: 227.6 °C
• Appearance: White or almost White Crystalline power
• Density: 1.0148 (rough estimate)
• Vapor Pressure: 1.4E-11mmHg at 25°C
• Refractive Index: 1.4840 (estimate)
• Storage Temp.: Sealed in dry,Room Temperature
• Solubility: Chloroform (Slightly), Methanol (Slightly)
• Merck: 4839
• CAS DataBase Reference: 17a-Hydroxyprogesterone caproate(CAS DataBase Reference)
• NIST Chemistry Reference: 17a-Hydroxyprogesterone caproate(630-56-8)
• EPA Substance Registry System: 17a-Hydroxyprogesterone caproate(630-56-8)

Safety Data

• Hazard Codes: T
• Statements: 61
• Safety Statements: 53-22-36/37/39-45
• WGK Germany: 3
• RTECS: TU5085000
• Hazardous Substances Data: 630-56-8(Hazardous Substances Data)

Usage

Uses

Used in Obstetrics and Gynecology:
17a-Hydroxyprogesterone caproate is used as a synthetic progestin for the prevention of spontaneous preterm births in singleton pregnancies in women who have previously had a spontaneous preterm birth. It is also used to reduce the chances of pre-term birth in women and improve specific fetal outcomes.
Used in Pharmaceutical Formulation:
A new formulation of 17a-Hydroxyprogesterone caproate, known as Makena (previously named as Gestiva), was deemed approvable by the FDA in late 2006 for the prevention of preterm labor, pending further studies. Makena was approved by the U.S. FDA on February 4, 2011, for the prevention of preterm delivery in women with a history of preterm delivery.

Originator

Delalutin,Squibb,US,1956

Manufacturing Process

40 grams of 17α-oxypregnene-(5)-ol-(3)-one-(20)-acetate-(3) is brought to reaction with 22 grams of p-toluolsulfonic acid and 850 cc of caproic acid anhydride under a nitrogen atmosphere for 5 days at room temperature or 2,5 days at 37°C. The excess anhydride is blown off with steam in the presence of 200 cc of pyridine and the distillation residue is extracted with ether and worked up as usual. The remaining oil is brought to crystallization with pentane and the raw 17α-oxypregnenolone-3-acetate-17-caproate is recrystallized from methanol. The crystals are needle-like and have a MP of 104° to 105°C. This substance is partially saponified by refluxing for 1 hour in 1,800 cc of methanol in the presence of 13 cc of concentrated hydrochloric acid. After evaporation of the methanol under vacuum, the dry residue is recrystallized from isopropyl ether or methanol (dense needles). The thus obtained 17α-oxypregnenolone-17-caproate melts at 145° to 146.5°C. By oxidation in 100 cc of absolute toluol with 425 cc of cyclohexanone and 155 cc of a 20% aluminum isopropylate solution in absolute toluol and after repeated crystallizations from isopropyl ether or methanol, 24 grams of pure 17α-oxyprogesterone-17-caproate is obtained, MP 119° to 121°C (dense needles).

Therapeutic Function

Progestin

Mechanism of action

Hydroxyprogesterone caproate is a synthetic progestin. Hydroxyprogesterone is a potent, long-acting, progestational steroid ester which transforms proliferative endothelium into secretory endothelium, induces mammary gland duct development, and inhibits the production and/or release of gonadotropic hormone; it also shows slight estrogenic, androgenic, or corticoid effects as well, but should not be relied upon for these effects. It's mechanism for preventing preterm birth in women with a history of preterm delivery is unknown.

Clinical Use

Hydroxyprogesterone caproate (Makena?) is used to reduce the risk of preterm birth in women with a singleton pregnancy who have a history of singleton spontaneous preterm birth. Hydroxyprogesterone caproate was designated an orphan drug by the US Food and Drug Administration (FDA) for this use in 2007. Efficacy of the drug for this use is based on improvement in the proportion of women who delivered at less than 37 weeks of gestation. Direct clinical benefit (e.g., improvement in neonatal morbidity and mortality) has not been established. While there are many risk factors for preterm birth, safety and efficacy of hydroxyprogesterone caproate have been demonstrated only in women with a prior spontaneous singleton birth. Hydroxyprogesterone is not intended for use in women with multiple gestations or other risk factors for preterm birth. The American College of Obstetricians and Gynecologists (ACOG) recommends that progesterone supplementation for the prevention of recurrent preterm birth be offered to women with a singleton pregnancy and a prior spontaneous preterm birth at less than 37 weeks of gestation due to spontaneous preterm labor or premature rupture of membranes. The ACOG also states that physicians should be able to prescribe Makena or compounded hydroxyprogesterone caproate based on accepted medical indications after discussion with the patient.

Safety

Originally marketed (Delalutin) nearly 50 years ago to prevent impending miscarriages, 17α-hydroxyprogesterone caproate was removed from the market in 2000 when its efficacy was called into question. 17α-Hydroxyprogesterone caproate, a synthetic injectable progesterone, was approved by the FDA in 2011 to reduce the risk of preterm delivery in women who have already experienced a preterm birth.It has not been shown to be effective in women carrying multiple fetuses.Injections begin between 16 and 21 weeks and are associated with pain, swelling, or itching at the injection site, hives, nausea, and diarrhea. Follow-up studies of the children born to women who used this drug indicate that developmental milestones were achieved at 2.5 and 5 years of age. A number of other pharmacologic agents are currently available for the prevention of preterm delivery including agents that can alter intracellular messengers (e.g., β-adrenergic receptor agonists, nitric oxide donors, magnesium sulfate and calcium channel blockers) and agents that modulate myometrial stimulants (e.g., inhibitors of prostaglandin synthesis and oxytocin antagonists). 17α-Hydroxyprogesterone caproate binds extensively to albumin and SHBG. From a metabolic perspective, it undergoes reduction， hydroxylation， and conjuga- tion reactions, including becoming glucuronidated, sulfated, and acetylated. It induces several cytochrome P450 (CYP) isozymes including CYP1A2, CYP2A6, and CYP2B6.

InChI:InChI=1/C27H40O4/c1-5-6-7-8-24(30)31-27(18(2)28)16-13-23-21-10-9-19-17-20(29)11-14-25(19,3)22(21)12-15-26(23,27)4/h17,21-23H,5-16H2,1-4H3/t21?,22?,23?,25-,26-,27-/m0/s1

Synthetic route

n-hexanoic anhydride (2051-49-2) + 17-hydroxyprogesterone (68-96-2) → 17-hexanoyloxy-pregn-4-ene-3,20-dione (630-56-8)

Conditions	Yield
With toluene-4-sulfonic acid

17-hexanoyloxy-3β-hydroxy-pregn-5-en-20-one (94201-44-2) → 17-hexanoyloxy-pregn-4-ene-3,20-dione (630-56-8)

Conditions	Yield
With cyclohexanone; aluminum isopropoxide
With cyclohexanone; aluminum isopropoxide

3β-formyloxy-17-hexanoyloxy-pregn-5-en-20-one (6084-02-2) → 17-hexanoyloxy-pregn-4-ene-3,20-dione (630-56-8)

Conditions	Yield
With cyclohexanone; aluminum isopropoxide
With cyclohexanone; aluminum isopropoxide

17-hydroxyprogesterone (68-96-2) + hexanoic acid (142-62-1) → 17-hexanoyloxy-pregn-4-ene-3,20-dione (630-56-8)

Conditions	Yield
With trifluoroacetic anhydride
Stage #1: 17-hydroxyprogesterone; hexanoic acid With pyridine; toluene-4-sulfonic acid In toluene at 110 - 120℃; for 3h; Stage #2: With hydrogenchloride In ethanol; water for 2h; Reagent/catalyst; Solvent; Reflux;	19.8 g

n-hexanoic anhydride (2051-49-2) → 17-hexanoyloxy-pregn-4-ene-3,20-dione (630-56-8)

Conditions	Yield
Multi-step reaction with 2 steps 1: toluene-4-sulfonic acid; benzene 2: cyclohexanone; aluminium isopropylate View Scheme
Multi-step reaction with 3 steps 1: toluene-4-sulfonic acid 2: hydrogenchloride 3: cyclohexanone; aluminum isopropoxide View Scheme

3β-formyloxy-17-hydroxy-pregn-5-en-20-one (20867-15-6) → 17-hexanoyloxy-pregn-4-ene-3,20-dione (630-56-8)

Conditions	Yield
Multi-step reaction with 2 steps 1: toluene-4-sulfonic acid; benzene 2: cyclohexanone; aluminium isopropylate View Scheme

3β-acetoxy-17-hexanoyloxy-pregn-5-en-20-one (86790-83-2) → 17-hexanoyloxy-pregn-4-ene-3,20-dione (630-56-8)

Conditions	Yield
Multi-step reaction with 2 steps 1: hydrogenchloride 2: cyclohexanone; aluminum isopropoxide View Scheme

17-hydroxyprogesterone (68-96-2) + hexanoic acid (142-62-1) → 17-hexanoyloxy-pregn-4-ene-3,20-dione (630-56-8) + C33H50O5

Conditions	Yield
With pyridine; toluene-4-sulfonic acid In toluene at 110 - 120℃; for 3h; Solvent;

17-hexanoyloxy-pregn-4-ene-3,20-dione (630-56-8) → 16-dehydroprogesterone (1096-38-4)

Conditions	Yield
	83%

17-hexanoyloxy-pregn-4-ene-3,20-dione (630-56-8) → 17α-Hydroxypregna-4,6-diene-3,20-dione 17-capronate (4975-65-9)

Conditions	Yield
With acetic anhydride; chloranil; 5-sulfosalicylic Acid In xylene for 6h; Heating;	40%

17-hexanoyloxy-pregn-4-ene-3,20-dione (630-56-8) → 17-hexanoyloxy-pregna-1,4-diene-3,20-dione (5588-40-9)

17-hexanoyloxy-pregn-4-ene-3,20-dione (630-56-8) → anti-17α-Caproyloxy-Δ4-pregnen-20-on-3-N-chlorimin + syn-17α-Caproyloxy-Δ4-pregnen-20-on-3-N-chlorimin

Conditions	Yield
(i) MeNH2, MeOH, (ii) aq. Ca(OCl)2, NH3, OTs; Multistep reaction;

17-hexanoyloxy-pregn-4-ene-3,20-dione (630-56-8) → Hexanoic acid (8R,9S,10R,13S,14S,17R)-3-acetoxy-17-acetyl-10,13-dimethyl-2,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-17-yl ester

17-hexanoyloxy-pregn-4-ene-3,20-dione (630-56-8) → Hexanoic acid (6S,8R,9S,10R,13S,14S,17R)-17-acetyl-6-hydroxy-10,13-dimethyl-3-oxo-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl ester + Hexanoic acid (6R,8R,9S,10R,13S,14S,17R)-17-acetyl-6-hydroxy-10,13-dimethyl-3-oxo-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl ester

Conditions	Yield
at 37℃; for 0.166667h; in incubation mixture, with rat liver microsomes; or perbenzoic acid oxidation of dienol acetate;

17-hexanoyloxy-pregn-4-ene-3,20-dione (630-56-8) → 3β,17α-Dihydroxypregna-4,6-dien-20-one 17-caproate (81089-15-8)

Conditions	Yield
Multi-step reaction with 2 steps 1: 40 percent / chloranil, sulfosalicylic acid, acetic anhydride / xylene / 6 h / Heating 2: 55 percent / sodium borohydride / methanol / 0.5 h / Ambient temperature View Scheme

17-hexanoyloxy-pregn-4-ene-3,20-dione (630-56-8) → Hexanoic acid (6S,8R,9S,10R,13S,14S,17R)-6-acetoxy-17-acetyl-10,13-dimethyl-3-oxo-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl ester

Conditions	Yield
Multi-step reaction with 2 steps 2: acetic acid / Ambient temperature; anodic oxidation; platinum electrode, potassium acetate electrolyte View Scheme

17-hexanoyloxy-pregn-4-ene-3,20-dione (630-56-8) → Hexanoic acid (6R,8R,9S,10R,13S,14S,17R)-6-acetoxy-17-acetyl-10,13-dimethyl-3-oxo-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl ester

Conditions	Yield
Multi-step reaction with 2 steps 2: acetic acid / Ambient temperature; anodic oxidation; platinum electrode, potassium acetate electrolyte View Scheme

Upstream product

• 68-96-2 17-hydroxyprogesterone 
• 142-62-1 hexanoic acid 
• 142-61-0 Hexanoyl chloride 
• 86790-83-2 3β-acetoxy-17-hexanoyloxy-pregn-5-en-20-one 
• 20867-15-6 3β-formyloxy-17-hydroxy-pregn-5-en-20-one 
• 2051-49-2 n-hexanoic anhydride 
• 6084-02-2 3β-formyloxy-17-hexanoyloxy-pregn-5-en-20-one 
• 94201-44-2 17-hexanoyloxy-3β-hydroxy-pregn-5-en-20-one 
• 1600-27-7 mercury(II) diacetate 
• 65851-76-5 17α-ethynyl-17β-nitro-oxy-4-androsten-3-one 
• 974-23-2 3β-hydroxy-16α,17α-epoxypregn-5-en-20-one 
• 14072-39-0 16β-bromo-3β,17α-dihydroxypregn-5-ene-20-one 
• 387-79-1 17-Hydroxypregnenolone 
• 570-58-1 5β-17α-hydroxy-preganene-3,20-dione 

Downstream Products

• 4954-07-8 pregna-3,5-dien-20-one, 3,17-dihydroxy-, diacetate 
• 32634-95-0 17α-Acetoxy-6-methylene-pregn-4-ene-3,20-dione 
• 1054-64-4 17α-acetoxy-3-methoxypregna-3,5-dien-20-one 
• 1096-38-4 16-dehydroprogesterone 
• 1616932-89-8 17α-p-iodophenylcarbamoiloxypregn-4,6-dien-3,20-dione 
• 1616932-88-7 17α-p-bromophenylcarbamoiloxypregn-4,6-dien-3,20-dione 
• 1616932-87-6 17α-p-chlorophenylcarbamoiloxypregn-4,6-dien-3,20-dione 
• 1616932-86-5 17α-p-fluorophenylcarbamoiloxypregn-4,6-dien-3,20-dione 
• 1616932-85-4 17α-phenylcarbamoiloxypregn-4,6-dien-3,20-dione 
• 1616932-84-3 17α-p-iodobenzoiloxy-4,6-pregnadien-3,20-dione 
• 1190878-48-8 17α-p-bromobenzoyloxy-4,6-pregnadiene-3,20-dione 
• 1190878-47-7 17α-p-chlorobenzoyloxy-4,6-pregnadiene-3,20-dione 
• 1190878-46-6 17α-p-fluorobenzoyloxy-4,6-pregnadiene-3,20-dione 
• 81480-72-0 17α-benzoyloxy-4,6-pregnadiene-3,20-dione 

Relevant articles and documents

Novel method for preparing progesterone caproate

The invention discloses a novel method for preparing progesterone caproate, which specifically comprises the following steps: 1) taking 17a-hydroxyprogesterone as an initial raw material, dissolving the raw material in a solvent, then dropwise adding hexanoyl chloride as an acylating agent, after dropwise adding, conducting heating to 30-40 DEG C, and carrying out heat preservation reaction to prepare a progesterone caproate solution; 2) cooling the progesterone hexanoate solution to room temperature, adding a sodium carbonate aqueous solution for neutralization reaction to generate a byproduct hydrogen chloride, ending the reaction until the pH value is 7, and after the reaction is finished, conducting filtering, conducting washing with water and conducting drying in vacuum to obtain a crude progesterone hexanoate product; and 3) recrystallizing the progesterone caproate crude product with ethanol to obtain a progesterone caproate refined product. According to the method, hexanoyl chloride is adopted as an acylating agent and is subjected to acylation reaction with 17a-hydroxyprogesterone to generate progesterone hexanoate and hydrogen chloride, so that the yield of progesterone hexanoate is greatly improved, meanwhile, the acylation reaction of ketone groups on the third position is effectively prevented by using hydrogen chloride, and byproducts such as hexanoic acid and ethyl hexanoate are prevented from being generated.

Preparation process of 17a-hydroxyprogesterone acetate

The invention discloses a preparation process of 17a-hydroxyprogesterone acetate. According to the invention, high-purity 17a-hydroxyprogesterone acetate is obtained sequentially through an acylation reaction, a hydrolysis reaction, a neutralization reaction, centrifugation and refining. Therefore, a process procedure is shortened, raw material input is reduced, and cost is saved.

Method for synthesis of progesterone-hexanoic acid (by machine translation)

The invention discloses a synthesis method of hydroxyprogesterone caproate, which comprises the following steps: 1. carrying out esterification reaction on 17alpha-hydroxy progesterone used as a raw material and n-hexanoic acid under the catalytic actions of pyridine and p-toluenesulfonic acid to obtain an esterified substance mixture; and 2. carrying out alcoholysis on the esterified substance mixture in the step 1 under the catalytic action of acid to obtain the hydroxyprogesterone caproate crude product. The methylbenzene, ethanol and other solvents used in the method are easy to recover and reutilize, thereby lowering the treatment cost of chemical pollutants; and the method avoids using the expensive n-caproic anhydride in the reaction process, thereby greatly lowering the auxiliary material cost and recovery cost. In the synthesis route, the yield of the hydroxyprogesterone caproate crude product is 115-120%, the refinement yield is 80%, and the total yield is up to 95%. Although the yield is not enhanced as compared with the traditional technique, the application of the noble auxiliary materials is reduced, thereby obviously enhancing the economic benefit.

THERAPEUTIC FOR HEPATIC CANCER

A novel pharmaceutical composition for treating or preventing hepatocellular carcinoma and a method of treatment are provided. A pharmaceutical composition for treating or preventing liver cancer is obtained by combining a chemotherapeutic agent with an anti-glypican 3 antibody. Also disclosed is a pharmaceutical composition for treating or preventing liver cancer which comprises as an active ingredient an anti-glypican 3 antibody for use in combination with a chemotherapeutic agent, or which comprises as an active ingredient a chemotherapeutic agent for use in combination with an anti-glypican 3 antibody. Using the chemotherapeutic agent and the anti-glypican 3 antibody in combination yields better therapeutic effects than using the chemotherapeutic agent alone, and mitigates side effects that arise from liver cancer treatment with the chemotherapeutic agent.

Anti-Claudin 3 Monoclonal Antibody and Treatment and Diagnosis of Cancer Using the Same

Monoclonal antibodies that bind specifically to Claudin 3 expressed on cell surface are provided. The antibodies of the present invention are useful for diagnosis of cancers that have enhanced expression of Claudin 3, such as ovarian cancer, prostate cancer, breast cancer, uterine cancer, liver cancer, lung cancer, pancreatic cancer, stomach cancer, bladder cancer, and colon cancer. The present invention provides monoclonal antibodies showing cytotoxic effects against cells of these cancers. Methods for inducing cell injury in Claudin 3-expressing cells and methods for suppressing proliferation of Claudin 3-expressing cells by contacting Claudin 3-expressing cells with a Claudin 3-binding antibody are disclosed. The present application also discloses methods for diagnosis or treatment of cancers.

Further syntheses of cyproterone acetate

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Microwave induced selective enolization of steroidal ketones and efficient acetylation of sterols in semisolid state

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15β-Hydroxysteroids (part V). Steroids of the human perinatal period: The synthesis of 3β, 15β, 17α-trihydroxy-5-pregnen-20- one from 15β, 17α-dihydroxy-4-pregnen-3,20-dione

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Anti-glaucomatous pharmaceutical composition and the process for obtaining them

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REDUCTIVE DEHALOGENATION OF 21-IODO DERIVATIVES OF CORTICOSTEROIDS

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