Editing Morphine (section)

== Production ==
[[File:Alkaloids.png|thumb|upright=1.3|First generation production of alkaloids from licit latex-derived opium]]
In the [[opium poppy]], the alkaloids are bound to [[meconic acid]]. The method is to extract from the crushed plant with diluted sulfuric acid, which is a stronger acid than meconic acid, but not so strong to react with alkaloid molecules. The [[Extraction (chemistry)|extraction]] is performed in multiple steps (one amount of crushed plant is extracted at least six to ten times, so practically every [[alkaloid]] goes into the solution). From the solution obtained at the last extraction step, the alkaloids are precipitated by either ammonium hydroxide or sodium carbonate. The last step is purifying and separating morphine from other opium alkaloids. The somewhat similar Gregory process was developed in the United Kingdom during the Second World War, which begins with stewing the entire plant, in most cases save the roots and leaves, in plain or mildly acidified water, then proceeding through steps of concentration, extraction, and purification of alkaloids.{{Citation needed|date=January 2014}} Other methods of processing "poppy straw" (i.e., dried pods and stalks) use steam, one or more of several types of alcohol, or other organic solvents.

The poppy straw methods predominate in Continental Europe and the British Commonwealth, with the latex method in most common use in India. The latex method can involve either vertical or horizontal slicing of the unripe pods with a two-to five-bladed knife with a guard developed specifically for this purpose to the depth of a fraction of a millimetre and scoring of the pods can be done up to five times. An alternative latex method sometimes used in China in the past is to cut off the poppy heads, run a large needle through them, and collect the dried latex 24 to 48 hours later.{{Citation needed|date=January 2014}}

In India, opium harvested by licensed poppy farmers is dehydrated to uniform levels of hydration at government processing centers and then sold to pharmaceutical companies that extract morphine from the opium. However, in Turkey and Tasmania, morphine is obtained by harvesting and processing the fully mature dry seed pods with attached stalks, called ''poppy straw''. In Turkey, a water extraction process is used, while in Tasmania, a solvent extraction process is used.<ref>{{cite report|url=https://www.ojp.gov/pdffiles1/Digitization/141189NCJRS.pdf#page=16 |page=16 |title=Opium Poppy Cultivation and Heroin Processing in Southeast Asia |date=September 1992 |publisher=US Department of Justice}}</ref>

Opium poppy contains at least 50 different alkaloids, but most of them are of low concentration. Morphine is the principal alkaloid in raw opium and constitutes roughly 8–19% of [[opium]] by dry weight (depending on growing conditions).<ref name="Jenkins AJ 2008" /> Some purpose-developed strains of poppy now produce opium that is up to 26% morphine by weight.{{Citation needed|date=January 2014}} A rough rule of thumb to determine the morphine content of pulverised dried poppy straw is to divide the percentage expected for the strain or crop via the latex method by eight or an empirically determined factor, which is often in the range of 5 to 15.{{Citation needed|date=January 2014}} The Norman strain of ''P. somniferum'', also developed in [[Tasmania]], produces down to 0.04% morphine but with much higher amounts of [[thebaine]] and [[oripavine]], which can be used to synthesise semi-synthetic opioids as well as other drugs like stimulants, emetics, opioid antagonists, anticholinergics, and smooth-muscle agents.{{Citation needed|date=January 2014}}

In the 1950s and 1960s, [[Hungary]] supplied nearly 60% of Europe's total medication-purpose morphine production. To this day, poppy farming is legal in Hungary, but poppy farms are limited by law to {{convert|2|acre|m2}}. It is also legal to sell dried poppies in flower shops for use in floral arrangements.

It was announced in 1973 that a team at the National Institutes of Health in the United States had developed a method for total synthesis of morphine, [[codeine]], and thebaine using coal tar as a starting material. A shortage in codeine-hydrocodone class cough suppressants (all of which can be made from morphine in one or more steps, as well as from codeine or thebaine) was the initial reason for the research.

Most morphine produced for pharmaceutical use around the world is converted into codeine as the concentration of the latter in both raw opium and poppy straw is much lower than that of morphine; in most countries, the usage of codeine (both as end-product and precursor) is at least equal or greater than that of morphine on a weight basis.

=== Chemical synthesis ===
{{Main|Morphine total synthesis}}
The first [[morphine total synthesis]], devised by [[Marshall D. Gates, Jr.]] in 1952, remains a widely used example of [[total synthesis]].<ref>{{cite journal |vauthors = Gates M, Tschudi G |title = The Synthesis of Morphine |journal = Journal of the American Chemical Society |date = April 1956 |volume = 78 |issue = 7 |pages = 1380–1393 |doi = 10.1021/ja01588a033 |bibcode = 1956JAChS..78.1380G }}</ref> Several other syntheses were reported, notably by the research groups of Rice,<ref>{{cite journal | vauthors = Rice KC |title = Synthetic opium alkaloids and derivatives. A short total synthesis of (±)-dihydrothebainone, (±)-dihydrocodeinone, and (±)-nordihydrocodeinone as an approach to a practical synthesis of morphine, codeine, and congeners |journal = The Journal of Organic Chemistry |date = July 1980 |volume = 45 |issue = 15 |pages = 3135–3137 |doi = 10.1021/jo01303a045 }}</ref> Evans,<ref>{{cite journal |vauthors = Evans DA, Mitch CH |title = Studies directed towards the total synthesis of morphine alkaloids |journal = Tetrahedron Letters |date = January 1982 |volume = 23 |issue = 3 |pages = 285–288 |doi = 10.1016/S0040-4039(00)86810-0 }}</ref> Fuchs,<ref>{{cite journal |vauthors = Toth JE, Hamann PR, Fuchs PL |title = Studies culminating in the total synthesis of (dl)-morphine |journal = The Journal of Organic Chemistry |date = September 1988 |volume = 53 |issue = 20 |pages = 4694–4708 |doi = 10.1021/jo00255a008 }}</ref> Parker,<ref>{{cite journal |vauthors = Parker KA, Fokas D |title = Convergent synthesis of (±)-dihydroisocodeine in 11 steps by the tandem radical cyclization strategy. A formal total synthesis of (±)-morphine |journal = Journal of the American Chemical Society |date = November 1992 |volume = 114 |issue = 24 |pages = 9688–9689 |doi = 10.1021/ja00050a075 }}</ref> Overman,<ref>{{cite journal |vauthors = Hong CY, Kado N, Overman LE |title = Asymmetric synthesis of either enantiomer of opium alkaloids and morphinans. Total synthesis of (−)- and (+)-dihydrocodeinone and (−)- and (+)-morphine |journal = Journal of the American Chemical Society |date = November 1993 |volume = 115 |issue = 23 |pages = 11028–11029 |doi = 10.1021/ja00076a086 |bibcode = 1993JAChS.11511028H }}</ref> Mulzer-Trauner,<ref>{{cite journal |vauthors = Mulzer J, Dürner G, Trauner D |title = Formal Total Synthesis of(—)-Morphine by Cuprate Conjugate Addition |journal = Angewandte Chemie International Edition in English |date = December 1996 |volume = 35 |issue = 2324 |pages = 2830–2832 |doi = 10.1002/anie.199628301 }}</ref> White,<ref>{{cite journal |vauthors = White JD, Hrnciar P, Stappenbeck F |title = Asymmetric Total Synthesis of (+)-Codeine via Intramolecular Carbenoid Insertion |journal = The Journal of Organic Chemistry |date = October 1999 |volume = 64 |issue = 21 |pages = 7871–7884 |doi = 10.1021/jo990905z }}</ref> Taber,<ref>{{cite journal | vauthors = Taber DF, Neubert TD, Rheingold AL | title = Synthesis of (-)-morphine | journal = Journal of the American Chemical Society | volume = 124 | issue = 42 | pages = 12416–7 | date = October 2002 | pmid = 12381175 | doi = 10.1021/ja027882h | s2cid = 32048193 }}</ref> Trost,<ref>{{cite journal | vauthors = Trost BM, Tang W | title = Enantioselective synthesis of (-)-codeine and (-)-morphine | journal = Journal of the American Chemical Society | volume = 124 | issue = 49 | pages = 14542–3 | date = December 2002 | pmid = 12465957 | doi = 10.1021/ja0283394 | url = https://figshare.com/articles/Enantioselective_Synthesis_of_-Codeine_and_-Morphine/3646293 }}</ref> Fukuyama,<ref>{{cite journal | vauthors = Uchida K, Yokoshima S, Kan T, Fukuyama T | title = Total synthesis of (+/-)-morphine | journal = Organic Letters | volume = 8 | issue = 23 | pages = 5311–3 | date = November 2006 | pmid = 17078705 | doi = 10.1021/ol062112m }}</ref> Guillou,<ref>{{cite journal | vauthors = Varin M, Barré E, Iorga B, Guillou C | title = Diastereoselective total synthesis of (+/-)-codeine | journal = Chemistry: A European Journal | volume = 14 | issue = 22 | pages = 6606–8 | year = 2008 | pmid = 18561354 | doi = 10.1002/chem.200800744 }}</ref> and Stork.<ref>{{cite journal | vauthors = Stork G, Yamashita A, Adams J, Schulte GR, Chesworth R, Miyazaki Y, Farmer JJ | title = Regiospecific and stereoselective syntheses of (+/-) morphine, codeine, and thebaine via a highly stereocontrolled intramolecular 4 + 2 cycloaddition leading to a phenanthrofuran system | journal = Journal of the American Chemical Society | volume = 131 | issue = 32 | pages = 11402–6 | date = August 2009 | pmid = 19624126 | doi = 10.1021/ja9038505 | url = https://figshare.com/articles/Regiospecific_and_Stereoselective_Syntheses_of_Morphine_Codeine_and_Thebaine_via_a_Highly_Stereocontrolled_Intramolecular_4_2_Cycloaddition_Leading_to_a_Phenanthrofuran_System/2834536 }}</ref> Because of the stereochemical complexity and consequent synthetic challenge presented by this [[Polycyclic compound|polycyclic]] structure, Michael Freemantle has expressed the view that it is "highly unlikely" that a chemical synthesis will ever be cost-effective such that it could compete with the cost of producing morphine from the opium poppy.<ref>{{cite web |url = http://pubs.acs.org/cen/coverstory/83/8325/8325morphine.html |title = The Top Pharmaceuticals That Changed The World-Morphine |publisher = Chemical and Engineering News | vauthors = Freemantle M |date = 20 June 2005 }}</ref>

===GMO synthesis===

====Research====
Thebaine has been produced by [[GMO]] ''[[E. coli]]''.<ref>{{cite web |title=Genetically modified E. coli pump out morphine precursor: Bacteria yield 300 times more opiates than yeast |url=https://www.sciencedaily.com/releases/2016/02/160225101103.htm |website=ScienceDaily |language=en}}</ref>