A Review of U.S. Patents in the Field of Organic Process Development Published during May and June 2015by Keith Turner

Organic Process Research & Development


Physical and Theoretical Chemistry / Organic Chemistry


A Review of U.S. Patents in the Field of Organic Process

Development Published during May and June 2015 ■ SUMMARY

The current review contains 20 patents from an original list that contained 315 that fit the selection criteria. A range of topics is covered that may generate interest among readers. A number of the patents cover fluorinated derivatives prepared using cheaper fluorinating agents, and there are examples of pharmaceuticals, agrochemicals, and compounds that are used in manufacturing lithium ion batteries. Indium is not a common reagent in organic chemistry, either as the metal or in the form of any of its compounds. A patent describes using indium metal in an acylation reaction in preference to Na or Li because it has a first ionization potential that is similar to Na or Li and is relatively air stable and has low toxicity. Further interest in the use of this metal may be expected. Typographical mistakes in patents are common, but some of the chemical mistakes are unacceptable.

An example is the statement in a patent that a silylated chloroacetylene with five C atoms is prepared from a propargyl alcohol and HCl. Proof reading by a chemist would prevent such errors. A number of the patents in this collection describe experiments carried out on a kilo or multikilo scale and thus suggesting an advanced stage of development or even commercial operation. However, there is no legal or commercial significance in the choice of patents in this review.

The advantages mentioned in this review are those claimed in the patent, unless this reviewer has personal knowledge of the subject. ■ PATENT NO. U.S. 9,029,547

Assignee: Muhammed Majeed et al., New Jersey, United


Title or Subject: Synthesis of 4-Aryl 4-Acylpiperidine, Its

Salts, and Its Analogues Using Indium Metal

This patent describes a method for the synthesis of the novel piperidine compound 7 that is the subject of the single claim of this patent. The patent reports that 4-acetyl-4-phenylpiperidine, 1c, has been investigated as a part of various drug molecules, but it is stated that its synthesis is not easy. One method is reported in J. Org. Chem. 1957, 22, 1484 and is outlined in

Scheme 1. This starts from compound 1a that is converted to 1b by a Grignard reaction. This is then subjected to hydrogenolysis using a Pd/C catalyst giving 1c. Compound 1a may also be converted to 1b using MeLi, and this is reported in the Japanese patent 2007119406.

The nitrile 1a can be prepared by a number of methods that are outlined in Scheme 2. The first route is a reaction between 2 and 3 that is catalyzed by strong bases. Reports include the use of sodamide, NaH, or NaOH with a phase transfer catalyst (PTC). An alternative route to 1a is by reaction of 4 and 5 in the presence of i-Pr2NEt and Tf2O.

The known routes to the desired compounds involve the use of hazardous reagents at temperatures of around −30 °C and are therefore not suitable for industrial production. The new route for preparing 1c that is described in this patent is shown in Scheme 3 and starts with the reaction of 6 with Ac2O in the presence of indium powder. This produces the novel diacetyl compound 7 that is isolated in 77% yield after purification by column chromatography (ColC). Analogous compounds were prepared using propionic, butyric, isobutyric, and benzoic anhydrides in place of Ac2O. In the next step 7 is reduced using a Pd/C catalyst to give the novel compound 1d (R = R1 = Ac) that is isolated in 82% yield. The 1H and 13C NMR data of the compounds 1d and 7 are provided. The HCl salt of 1c is obtained from 1d by treatment with NaOH followed by dil.

HCl, and the salt is isolated in 81.8% yield.

There are a number of reasons for using indium, and one is that it has a first ionization potential that is similar to that of Na

Scheme 1a aReagents and conditions: (a) MeMgBr or MeLi. (b) Pd/C, H2.

Scheme 2a aReagents and conditions: (a) NaH, NaOH/PTC, or NaNH2. (b) iPr2NEt/Tf2O.

Scheme 3a aReagents and conditions: (a) (i) In powder, HOAc, 100 °C, 6 h; (ii) cool to rt, add H2O; (iii) rt, 1 h; (iv) add EtOAc, filter; (v) separate, wash in NaHCO3, H2O wash, brine wash; (vi) dry, ColC. (b) (i) Pd/

C, MeOH, H2, 6 kg/m 2, 60 °C, 10 h; (ii) cool to rt, filter; (iii) concentrate, add i-PrOH, filter, dry. (c) (i) NaOH, H2O, MeOH, rt, 10 h; (ii) add dil HCl to pH 2; (iii) filter, concentrate, add i-PrOH, filter, dry.

Highlights from the Patents pubs.acs.org/OPRD © XXXX American Chemical Society A DOI: 10.1021/acs.oprd.5b00320

Org. Process Res. Dev. XXXX, XXX, XXX−XXX or Li; hence it may be easy for In to promote single electron transfer processes. The metal is also comparatively air stable and has low toxicity; it is also stated that unlike Zn, which gave moderate conversion, it gives higher yields. A mechanism for the action of In in the acetylation is provided in the patent and outlined in Scheme 4, but there is no discussion.

Advantages. The process gives a good yield for a novel route to the desired compound via a novel intermediate. ■ PATENT NOS. U.S. 9,029,555 AND U.S. 9,029,556

Assignee: Dow AgroScience LLC., Indianapolis, Indiana,

United States

Title or Subject: Process for the Preparation of 3-(3Chloro-1H-Pyrazol-1-yl)Pyridine

These two patents describe different methods of preparing 3a, a compound that is used as an intermediate in the production of pesticides which have the general formula 3b (R = amine, amide, or carabamate). A patent application assigned to Dow AgroScience (US 20130288893) describes the preparation of 3a and then its conversion to a very large number of compounds with structure 3b. The preparation of 3a is by direct coupling of 1 and 2 as shown in Scheme 5. This gives a low yield of 3a, and because pure 2 is difficult to isolate, a better process for preparing 3a is deemed to be desirable.

The route to prepare 3a that is described in the first patent is shown in Scheme 6 and involves the reaction of 4 with the commercially available nitrile 5 in the presence of NaOEt. This forms the aminopyrazole 6 that is recovered as a dark brown solid with 95% purity. The amine is then converted to the diazonium salt 7 that is not isolated but treated with CuCl to form crude 3a which is isolated in 65% yield and 73.7% purity.