Pharmaceutical Chemistry Patent Blog

Scheme:

The Mannich Reaction is an important carbon-carbon-bond forming reaction that is commonly employed in the synthesis of alkaloid natural products and is involved in a number of biosynthetic pathways. The reaction uses three components: an amine, a non-enolizable aldehyde or ketone, and a compound containing an enolizable carbonyl moiety. The final product of the reaction is a β-amino-carbonyl compound.

Mechanism:

The amine and non-enolizable aldehyde or ketone react to form an iminium ion or “Schiff base”. The second carbonyl compound tautomerizes to the enol form and attacks the iminium ion at the electrophilic carbon atom. The reaction typically requires long reaction times and elevated temperature under acidic conditions.

The reaction has continued to enjoy frequent use by synthetic chemists and has been employed in a several of the most important accomplishments in organic synthesis including strychnine, quinine, and atropine. The reaction has been extended by the discovery that a catalytic amount of (S)-proline, an inexpensive and naturally occurring amino acid, can be used to control the stereoselectivity of the reaction and provide products with high ee (enantiomeric excess).

Experimental Procedure:

For an example of the laboratory procedure for the Mannich reaction, see the synthesis of 4-(diethylamino)butan-2-one.

References:

Cordova, A.; Watanabe, S.; Tanaka, F.; Notz, W.; Barbas, C. F., III (2002). “A Highly Enantioselective Route to Either Enantiomer of Both α- and β-Amino Acid Derivatives”. Journal of the American Chemical Society 124 (9): 1866–1867. doi:10.1021/ja017833p.

Mannich, C.; Krosche, W. (1912). “Ueber ein Kondensationsprodukt aus Formaldehyd, Ammoniak und Antipyrin”. Archiv der Pharmazie 250: 647–667. doi:10.1002/ardp.19122500151.

Mitsumori S., Zhang H., Ha-Yeon Cheong P., Houk K. N.,Tanaka F., Barbas III C. F. (2006). “Direct Asymmetric anti-Mannich-Type Reactions Catalyzed by a Designed Amino Acid”. Journal of the American Chemical Society 128 (4): 1040–1041. doi:10.1021/ja056984f.

Diamond v. Diehr, 450 U.S. 175 (1981).

Argued October 14, 1980. Decided March 3, 1981.

Facts: The PTO rejected claims in Diehr’s patent directed to a process for curing rubber. The Patent Office contended that steps that are performed by a computer by means of a stored program do not constitute statutory subject matter under 35 USC 101. On appeal, the PTO Board of Appeals upheld the examiner’s rejection. On appeal to the Court of Customs and Patent Appeals, the Court reversed, finding in favor of Diehr.

Issue:Are otherwise valid claims rendered invalid by including mathematical formulas?

Holding: Claims that include mathematical formulae are not necessarily invalid. A process is “an act, or a series of acts, performed upon the subject-matter to be transformed and reduced to a different state or thing. If new and useful, it is just as patentable as is a piece of machinery. . . . The machinery pointed out as suitable to perform the process may or may not be new or patentable.”

The mere use of a mathematical formula, computer program, or digital computer does not render a process unpatentable. The claims must be considered as a whole; if the structure or process, when considered as a whole, is otherwise patentable subject matter, the utility requirements of 35 USC 101 are satisfied.

Disposition: Affirmed.

Notes:

Diamond v. Diehr was instrumental in paving the way for State Street v. Signature Financial and the patentability of business methods.

Diamond v. Chakrabarty was also instrumental in establishing the Court of Appeals for the Federal Circuit’s expansive approach to patentable subject matter: “the Supreme Court has acknowledged that Congress intended § 101 to extend to anything under the sun that is made by man.”

Diamond v. Chakrabarty, 447 U.S. 303 (1980).

Argued March 17, 1980. Decided June 16, 1980.

Facts:

Chakrabarty filed a patent application directed to an oil-eating bacterium. The PTO rejected a claim to the bacterium itself on the grounds that living matter is not patentable subject matter. The Board of Patent Appeals and Interferences upheld the examiner’s rejection. The rejection was overturned on appeal to the US Court of Customs and Patent Appeals and the US Supreme Court granted certiorari.

Issue: Are human-made micro-organisms patentable subject matter?

Holding:

Living organisms are patentable subject matter under 35 USC 101 and Chakrabarty’s micro-organism constitutes a “manufacture” or “composition of matter” within the meaning of that statute. The Court held that the terms “manufacture” and “composition of matter” are to be given a broad construction.

The court noted that the judiciary must be cautious when contemplating expanding patent law to new areas that Congress had not foreseen. The court noted however that title 35 contains no ambiguity and was to be construed broadly. The PTO also argued that the court should reject the patenting of living organisms as against public policy. The court held that such a determination was the province of the judiciary and held that the oil-eating bacterium was patentable subject matter.

The Williamson ether synthesis is a nucleophilic substitution reaction that leads to the formation of an ether by reacting an alkyl halide with an alkoxide ion:

The reaction can also be used to prepare an ether from two alcohol starting materials by first converting the OH moiety on one of the alcohols to a better leaving group such as tosylate, nosylate, brosylate, trifluoromethanesulfonate, or other sulfonate.

The reaction works best with primary alkyl halides and alcohols. Tertiary alkyl halides will not undergo an S_N2 displacement. Depending on the alkoxide, either elimination products (by either an E1 or E2 mechanism) or S_N1 products generally will be observed.

Mechanism:

The reaction proceeds primarily through an S_N2 (second order nucleophilic substitution) mechanism, particularly when a primary alkyl halide is used. The reaction can also proceed through an S_N1 (first order nucleophilic substitution) mechanism. E1 and E2 elimination products can also be observed when secondary alkyl halides are used.

The reaction rate for alkyl chlorides and bromides can be improved by adding a catalytic amount of sodium iodide to the reaction in a variation known as the Finkelstein reaction. The highly nucleophilic iodide ion displaces chloride or bromide to form an alkyl iodide intermediate which then reacts with the alkoxide.

Experimental Procedure:

See 3-(2-methoxyethoxy)prop-1-ene for an example of the laboratory procedure.

Esters are a class of functional groups and chemical compounds. Esters consist of an organic or inorganic acid in which the -OH group of the acid is replaced by an -OR group. Cyclic esters are usually called lactones. Some acids that are commonly esterified are carboxylic acids, phosphoric acid, nitric acid, and sulfuric acid. Volatile esters, particularly carboxylate esters, often have a pleasant smell and are found in essential oils, perfumes, and pheromones, and give many fruits their characteristic scent. Methyl acetate and ethyl acetate are important solvents; phosphoesters form the backbone of DNA molecules; fats and lipids are the esters of fatty acids; and polyesters are important synthetic fabrics and plastics. Esters can be synthesized in a condensation reaction between an acid and an alcohol in a reaction known as esterification.

Nomenclature

An ester is named according to the two parts that make it up: the part from the alcohol and the part from the acid (in that order), for example ethyl ethanoate (see image below).

For esters derived from the simplest carboxylic acids, the traditional name for the acid constituent is generally retained; for example, formate, acetate, propionate, butyrate. For esters from more complex carboxylic acids, the systematic name for the acid is used, followed by the suffix -oate. For example, methyl formate is the ester of methanol and methanoic acid (formic acid). It could also be called methyl methanoate.

Physical properties

Esters participate in hydrogen bonds as hydrogen-bond acceptors, but unlike their parent alcohols cannot act as hydrogen-bond donors. This ability to participate in hydrogen bonding makes them more water-soluble than their parent hydrocarbons; however, the limitations on their hydrogen bonding also make them more hydrophobic than either their parent alcohols or their parent acids. Their lack of hydrogen-bond-donating ability means that ester molecules cannot hydrogen-bond to each other, which, in general, makes esters more volatile than a carboxylic acid of similar molecular weight. This property makes them very useful in organic analytical chemistry: Unknown organic acids with low volatility can often be esterified into a volatile ester, which can then be analyzed using mass spectrometry, gas chromatography, or gas liquid chromatography. Many esters have distinctive odors and are used as artificial fragrances and flavorings.

Reactions

• Saponification (basic hydrolysis)
• Hydrolysis - the breakdown of an ester by water. This process can be catalyzed by both acids and bases. The base-catalyzed process is called saponification. The hydrolysis yields an alcohol and a carboxylic acid or its carboxylate salt.
• Reaction with primary or secondary amines to form amides.
• Phenyl esters react to form hydroxyarylketones via the Fries rearrangement.
• Esters are converted to isocyanates through intermediate hydroxamic acids in the Lossen rearrangement.
• Di-ester enolates such as diethyl malonate react as nucleophiles with alkyl halides in the malonic ester synthesis.
• Certain esters are functionalized with an α-hydroxyl group via the Chan rearrangement.
• Esters with β-hydrogen atoms can be converted to alkenes via pyrolysis.

Synthesis

Methods of preparing esters include:

• Transesterification.
• Dieckmann condensation or Claisen condensation.
• Favorskii rearrangement of α-haloketones in the presence of base.
• Pinner reaction of a nitrile with an alcohol.
• Nucleophilic displacement of alkyl halides with carboxylic acid salts.
• Nucleophilic displacement of acyl halides with alcohols.
• Baeyer-Villiger oxidation of ketones with peroxides.

A benzyl group is a substituent or molecular fragment possessing the structure C₆H₅CH₂-. The abbreviation “Bn” is commonly used in nomenclature and structural depictions of chemical compounds.

The term is also used in reference to the anion, carbocation, and free radical moieties featuring a benzene ring attached to a CH₂ group, in which the CH₂ group bears a negative charge, a positive charge, or a single unpaired electron respectively. In each case, the charge or radical electron is delocalized throughout the aromatic ring. The corresponding species is therefore much more stable than that of an ordinary primary anion, carbocation, or free radical.

This enhanced stability is observed in the Finkelstein reaction. Benzyl chloride has the same rate of reaction toward iodide as methyl chloride despite that methyl chloride is significantly more susceptible to S_N2 nucleophilic attack. While both benzyl chloride and n-butyl chloride are primary alkyl halides, the rate of reaction of benzyl chloride is 179 times greater.

Protective Groups

Benzyl groups frequently can be introduced to alcohol and carboxylic acids and subsequently removed easily and in high yield; therefore they are frequently used in organic synthesis as protective groups.

The following are two common methods for the protection of alcohols as the corresponding benzyl ethers:

• reaction of an alcohol with benzyl bromide and a strong base via Williamson ether synthesis.
• reaction of alcohol with an imidate such as benzyl trichloroacetimidate (C₆H₅CH₂OC(CCl₃)=NH) promoted by trifluoromethanesulfonic acid.

The following is an example of the use of a p-methoxybenzyl (PMB) ether in total synthesis:

The group can be removed readily by hydrogenation or by using CAN, DDQ, or magnesium bromide–dimethyl sulfide.

The following example demonstrates the use of a benzyl pyridinium salt as a benzyl donor for alcohols:

The solvent is α,α,α-trifluorotoluene and MgO is an acid scavenger. The reaction is believed to proceed via an S_N1 mechanism because Friedel-Crafts reaction side products are observed when toluene is used as a solvent.

Sanofi-Synthelabo v. Apotex, Inc., 470 F.3d 1368 (Fed. Cir. 2006).

Generic drug manufacturer Apotex wanted to market a generic form of Sanofi’s Plavix (clopidogrel bisulfate) and filed an ANDA alleging that Sanofi’s patents were invalid.

The two parties worked together to negotiate a settlement. The agreement was not accepted by state attorneys general even after new terms were presented. Under provisions of the agreement, the regulatory denial killed the settlement and the parties resumed litigation.

Sanofi then filed a motion for preliminary injunction to stop Apotex from selling its product. Within 21 days, the district court issued a preliminary injunction. During that time, Apotex shipped six-months of product. Apotex then appealed. In order to be granted a preliminary injunction, a party must show:

• Reasonable likelihood of success on the merits
• Irreparable harm if an injunction is not issued
• Balance of hardships tipped in favor of the party
• Injunction would have no negative impact on the public interest

The major difference between the factors for consideration in preliminary injunctive relief and those for permanent relief is that preliminary relief requires a showing of a likelihood of success while permanent relief requires success on the merits as a precondition. Thus, the final three factors will give some indication of how the court will rule in post-eBay injunction cases.

Likelihood of success on the merits: Apotex argued anticipation based on a broadly worded claim of a prior art patent that was considered by the examiner during prosecution. The court confirmed that this made the burden of proving invalidity at trial “especially difficult.” On obviousness, the CAFC confirmed that the unpredictability of enantiomer activity made the claimed dextrorotatory formation nonobvious even if the molecule as a whole was known.

Irreparable Harm: The settlement agreement between the parties included a provision that capped any damages for infringement by Apotex — seemingly an admission that Sanofi would settle for money damages. The court did not buy-into this argument because the agreement also contemplated an injunction.

Balance of hardships tip in Sanofi’s favor because Apotex chose to launch its product under threat of injunctive relief. It could have avoided the situation altogether and thus should not benefit from this factor.

Public Interest:

The court found no error in the lower court’s conclusion “that the significant public interest in encouraging investment in drug development and protecting the exclusionary rights conveyed in valid pharmaceutical patents” outweighs the public interest concerns offered by generic manufacturers and amici, including possible deaths due to patients opting to forgo purchasing medicine because of the lack of a less expensive alternative.

Eli Lilly & Co. v. Zenith Goldline Pharms., Inc. 471 F.3d 1369 (Fed. Cir. 2006).

Background: Lilly obtained a patent directed to olanzapine (Zyprexa®) and its use for the treatment of schizophrenia. The defendant generic manufacturers filed an ANDA and Lilly responded by filing a complaint in the Southern District of Indiana. After a bench trial, the district court found in favor of Lilly and held that the patent was valid, enforceable, and infringed. The defendants appealed to the Court of Appeals of the Federal Circuit.

Anticipation: To anticipate an invention, a prior art reference “must disclose each and every feature of the claimed invention, either explicitly or inherently.” In both Petering and Schaumann, prior art references that disclosed the family of the claimed compound were found to anticipate the claimed compounds even though the claimed compounds were not specifically identified. Here, the CAFC found that those cases were not applicable because the closest reference to olanzapine did not spell out “a definite and limited class of compounds that enabled a person of ordinary skill in the art to at once envisage each member in this limited class.”

Obviousness: The CAFC agreed that the prior art references did not suggest the compound. In addition, Lilly provided strong evidence of secondary indicia of nonobviousness including: “(1) a long-felt and unmet need; (2) failure of others; (3) industry acclaim; and (4) unexpected results.”

Public Use: Lilly conducted Phase I clinical trials before filing the application. The court found that the trials were well within the experimental use exception:

“In this case, Lilly tailored its tests to their experimental drug safety and efficacy purpose, adequately monitored for results, and maintained confidentiality throughout the duration of the study. The trial court did not err in finding no public use.”

Aventis Pharma & King Pharma v. Lupin Ltd. (Fed. Cir. 2007).

Altace is the King/Aventis brand of ramipril – a top-selling ACE inhibitor. The patent claims ramipril formulated “substantially free of other isomers.” The district court found the patent not invalid, but only by a slim margin. On appeal the CAFC reversed – finding the patent invalid as obvious.

Prior Art: One reference (‘944 patent) was filed as a continuation-in-part of an already abandoned patent application. That application was eventually revived, but Aventis argued on appeal that the ‘944 patent should not be awarded the filing date of the parent. The CAFC found this a potentially interesting argument, but refused to hear the argument because Aventis had failed to make the argument at the district court level.

The appellate panel also agreed that the experimental results of a Shering Doctor constituted 102(g)/103(a) prior art because the Doctor had not abandoned, suppressed, or concealed her prior invention.

Obviousness of a Purified Form: The district court, ruling pre-KSR, found the patent nonobvious. On appeal, the CAFC took a different view – finding that the purified form of a known mixture is prima facie obvious if a PHOSITA would have some reason to believe that the mixture derives properties from particular components.

However, if it is known that some desirable property of a mixture derives in whole or in part from a particular one of its components, or if the prior art would provide a person of ordinary skill in the art with reason to believe that this is so, the purified compound is prima facie obvious over the mixture even without an explicit teaching that the ingredient should be concentrated or purified.

The prima facie case of obviousness is especially difficult to rebut where, as here, the potency of the mixture varies directly with the amount of isomer in the mixture.

The court implicitly distinguished this case from Forest Labs — noting that obviousness may be rebutted by showing difficulty in purifying the mixture.

[A] purified compound is not always prima facie obvious over the mixture; for example, it may not be known that the purified compound is present in or an active ingredient of the mixture, or the state of the art may be such that discovering how to perform the purification is an invention of patentable weight in itself.

Reversed, Patent Invalid as Obvious