COPY No..ITEM No. 24FILE No. X—14 and XII—23

THE NX ORGANONPHARMACEUTICAL FACTORY

COMBINED INTELLIGENCE OBJECTIVESSUB-COMMITTEE

THE N. V. ORGANON'PHARMACEUTICAL FACTORYOSS, HOLLAND

Report by

Lt. Colonel H. J. PH2LPS

CIOS Black List Item 24Medical

COMBINED INTELLIGENCE OBJECTIVES"SUB COMMITTEEG-2 DIVISION, SHASF <Rear) APO 413

TABLE OF CONTENTS

Page No.

I. Visit to N*V. Organon at Oss.Holland (3-11 November 1944) 3

History of the Organon Factory duringthe Occupat ion.........�, 3

Technical Information...... f ., .......• 6

II. Discussions with Dr. Lenz 9

Table 1. Requirements for RestartingProduction.. 12

Appendix I Developments In the Prep-aration of SyntheticHormones... 13

" II Periston 14n III Application of Capain in

Shock 15» IV Vitamin C 18»» V Vitamin A 19* VI liarfan 11 20" VII Dolantln,,... 23" VIII Ge sarol ......... 2411 IX Penicillin 25M X List of Shortages 26

I. VISIT TO N.V. ORGANON at OSS - HOLLAND

Target No. 24/21The Organon pharmaceuticals factory at Oss

was visited on November 3rd, 9th, 10th and 11th,1944* My first visit confirmed our suspicionsthat this factory had been under the control ofSobering of Berlin throughout most of the occupa-tional period, and had been an important centreof manufacture of this concern after the bombingof their plants in the Berlin area. It was alsoapparent that the Germans haa left Oss in apanic and had left all the installations and manyrecords behind. I had the most amazing co-opera-tion from Dr. Tausk, Managing Director of theplant, who mobilised the whole of his high leveltechnical staff to assist me by sorting and trans-lating available information on the more importantitems of manufacture. I then spent two days indiscussing the material available with Dr; Tauskand his various specialists, the Organon Companyproviding the services of an English-speakingstenographer who took notes on these discussionswhich form the basis of the technical appendicesto the present report.

History of the Organon Factory during the Occupation

The Organon Factory lies a little to theeast of Oss railway station, adjacent to the VanZwanenberg meat packing factory which Organonobtained supplies of animal glands for extraction)and the Hartog margarine plant, the three factoriesforming what is.virtually one industrial complex.

The directors of the company left Oss theday after the German invasion of Holland in anattempt to reach England with important technicalinformation and considerable stocks of some rarerdrugs, particularly insulin. The party becameseparated and although two of the Dutch directorsand an English manager, who was visiting thefactory at the time, eventually reached England,Dr. Tausk was unable to do so. He returned to Osson the 15th May 1940 and for some time neither henor the company were interfered with by the Germans,

although the controlling interest of the Organonfactory appears to lie with the Van Zwanenbergcombine, in which there is a large Jewish inter-est. In November 194-0 the occupying authoritiesdeclared the Organon concern to be confiscated asa Jewish business and the shares were vested ina German trading company which had been set up inHolland to act as a receiver and custodian ofJewish property. Dr. Tausk was dismissed fromthe position of Managing Director, but when heapplied shortly afterwards in his own name for theposition of Director of Laboratories he waspromptly engaged and filled fchis position through-out' the occupation. A Dr. Duden of the SoberingCompany was appointed Trustee of the Organon fac-tory. Dr. Duden was not a technical man andinterfered very little in the operations of thefactory which continued with its pre-war.activi-ties but on a greatly reduced scale.

Early in 194-2 the Sobering concern formallytook over Organon N.V. by purchasing the shareswhich had been sequested by the German tradingcompany acting as Custodian for Jewish property.From this time the factory was worked entirelyas a Sobering concern, and a Dr. Zastrow, one ofthe leading chemists of Sobering A.G., came toOss as technical director of the factory.Sobering began immediately to enlarge the factoryand to install new plant. New buildings wereerected and the staff was increased. In the R.A.F.attacks on Berlin in February 194-4 Sobering ! soffices, laboratories, and tabletting and ampoul-ing plants, were entirely destroyed, and much ofthe other manufacturing capacity severely damaged.In consequence Sobering transferred a considerablepart of their manufacturing activities to Oss andthe enlargement of the factory was accelerated.The installation of h&w plant at Oss continued with-out a break during the early days of the Alliedlanding on the Continent, and work was actuallyproceeding on the equipment of a new building upto the 4th September 1944* On this day the B.B.C.broadcast a false rumour that the British Forcesadvancing from Brussels had reached Breda. TheGermans in the Organon factory and all Germancivilians in Oss, left the town in a panic andnever returned, although British forces did notreach Oss until the airborne invasion of 17thSeptember.

The chief activity of the Schering Companyat Oss centred on the manufacture of hormonepreparations. The production of insulin, whichwas normally one of the principal activities ofthe Organon factory, was continued on a reducedscale but large quantities of oesterone weremade by a new synthetic method devised by Scher-ing, while the production of cortisterone andtestosterone was also pushed forward and newtechnical methods were employed. A new methodof the synthesis of Vitamin C was introduced andresearch on the production of a syntheticVitamin A was carried to the point of producinga synthetic chemical with about one-tenth ofthe biological activity of natural vitamin A.A considerable amount of work was also done onthe preparation of a synthetic plasma substituteknown as Capain, which can now be made on acommercial scale and which appears to havegiven most satisfactory results in treatment.

The Schering Company was engaged in activeresearch on penicillin, but this work was notcarried out at Oss. From information which theDutch technical people at Oss had obtained fromthe Germans, it is apparent that Schering hadnot had much success with this work. On theother hand, the Dutch experts at Oss, and particu-larly Dr. Tausk, had been able to carry outsome research secretly on pencillin and had dis-covered a strain of moulds which gave a high yieldof very active antibacterial substance. It is notas yet certain whether this substance is identicalwith penicillin. The important cultures arenow believed to be held by Professor Julius ofUtrecht and when this town is liberated it wouldseem important to contact Professor Julius andobtain from him a sample of the mould which hadbeen used.

Throughout the occupational period theof the Organon factory:appear to have been veryactive in the resistance movement, and many ofthem certainly displayed remarkable courage. Twoof the Organon technical managers were, unfortunately, arrested for their activities. Dr. Boerrigter,who was a most courageous leader of the resistancegroup, was arrested in 1941 and sentenced to twelveyears imprisonment by the local military court.This sentence was, however, referred back to thelocal Summary court by Berlin and commuted by themto the death sentence.

Dr. Boerrigter was executed in 194-2. At the sametime Dr. Geerling was sentenced to four yearsimprisonment and is still in Germany.

TechnicalInformation

The chief points of technical informationwhich were obtained from the records left in thefactory, and from the personal knowledge of theDutch technical staff, were the following:- (tech-nical details are set out in appendices to thisreport, numbered as shown below).1. New developments in the commercial preparation

of synthetic hormones. (Appendix I).

2. The preparation and use of plasma substitutes.

These were, of two types:-

(a) An entirely synthetic substitute forblood liquid which was a colloidal poly-mer of polyvinyl-pyrrolidon, known bvthe Germans as PERISTON (Appendix II).

(b) A colloid polypeptide prepared fromcasein and known as CAPAIN (Appendix III)which appears to be quite free from anytoxic effects and which may be regardedas a complete protein substitute. Fulldetails for the manufacture of this sub-stance were obtained.

3• New Developments in Vitamin Chemistry. A newmethod for the preparation of vitamin C has beenevolved which avoids the use of potessium perman-ganate and of large quantities of acetone, both ofwhich substances were in short supply in Germany.The new process also evades th« existing patentson the production of synthetic Vitamin C.- It is,however, admitted tnat the yield of vitamin is lessgood than that obtained by the standard process ofmanufacture (Appendix IV). Research on the prod-uction of synthetic Vitamin A was prompted by thefact that supplies of Vitamin A were deficient inGermany. So far these researches have succeededin producing a substance with about one-tenth ofthe biological activity of natural Vitamin A, butprospects for the full synthesis of Vitamin Aappear to be good. (Appendix V.)

4. Marfaall arid Sulpha Drugs. The Germans havedone a great deal of work on the preparation anduse of MARFANID and a similar compound known asTIBATIN. Methods for the quantity production ofMarfanil have been worked out, and it appearsto have been used particularly in associationwith sulphanilamiae. There appeared to be noevidence of the use of Marfaril and pencil Lin incombination, but this may be due to the factthat the Germans have not apparently succeededin preparing penicillin in considerable quantity.(Appendix VI). No other significant developmentsin sulpha drugs were apparent, sulphanilamiaeand sulphathiazol being the drugs most commonlyused.

5. Synthetic Substitutes for Morphine. It wasconfirmed that the Germans were preparing consider-able quantities of DOLANTIN, and this substancecould in fact be purchased in many stores in Bel-gium and Holland. Since the preparation ofDolantin is known in the U.K. and the U.S.A.,information was collected only on the applicationsof Dolantin and on the question as to whether ornot the drug causes adaiction. (Appendix VII).

6. Anti-louse Powders. The only insecticidein which the experts at Oss knew the Germans to beinterested was GESAROL. This substance is almostcertainly less effective than D.D.T., and no infor-mation was collected on its methods of preparation,which are in any case generally known. A shortnote on the toxicity of Gesarol was prepared.

(Appendix VIII).

7• Penicillin ana Anti-bacterial Substancesextracted from Moulds. The Germans, and

particularly Sobering, has carried out intensiveresearch on Penicillin, and haa obtained strainsof Penicillium notatura from Professor Vvesterdijk,who has in her laboratories what is believed tobe the largest collection of moulds in the world.Apparently, however, the particular strain ofpenicillium notatum which Professor Vvesterdijkdeliverea to Schering was remarkably inactive asregards penicillin formation. Whether thisstrange circumstance was an accident or due toremarkable ingenuity on the part of ProfessorMesterdijk could not be ascertained with certainty,as tie Organon technicians preferred to keep a dis-creet silence on the matter, but it was aamitted

jtbat Professor Iftesterdijk had very active penicillinContaining cultures on which she had done consider-able secret research in association with ProfessorJulius of Utrecht and Dr. Tausk of Organon.

IX).

8. Anti-Malarials. No information was availableat the Organon factory regarding any new develop-,raents in the manufacture of syntheticDr. Tausk was of the opinion that there had beenno advances on atebrin and plasmoquin, and that therehad been no changes in the methods used to prepare .

these substances. It was confirmed that there hadbeen an increase in the use of the total mixed alka-loids of cinchona instead of refined quinine inthe treatment of malaria in order to conserve asfar as possible stocks of bark.

9. Dr. Tausk prepared for me a list of chemicalsand chemical apparatus which were in short supplyduring the occupation, with comments specificallyon the experiences of tne Organon factory (AppendixX.). I also attach a note on the stocks «of rawmaterials of various products and the requirementsfor the restarting of manufacture in variousbranches of the factory as at the time of my visit.(Table I folio-wing Section II). This informationwas also handed to the local civil affairs authori-ties who had passed it to 30 Corps, S.C.A.O., underreference CA/504/I - 3*

H.J.PHELPS.Lt.Col.E.A.B.6(d).

SECRET

II. Discussions with Dr. Lenz, ofOrganon N.V. Oss.

In the course of my stay at Oss I had theopportunity of several discussions with Dr. Lenz,Director of the Chemical Departments of OrganonN.V., who was employed in the Dutch Chemical War-fare Service in 1940* The following is a briefsummary of the information given by him \

Immediately after the occupation of Holland,the Germans examined the Dutch chemical warfarelaboratories at Delft, but although all the recordshad been destroyed the Dutch technicians wereasked very few questions. Practically all theDutch technicians were allowed to depart, or weredismissed, and a limited amount of research wascontinued, mainly by Germans, on the penetrationof vesicants through different types of protectiveclothing. The people working in these laboratorieswere interested both in mustard and in "nitrogenmustard". The Germans were plainly interestedboth in protective clothing against "nitrogenmustard" and in finding a suitable decontaminant.During the latter part of 1940 and early 1941 theydid not seem to have had much success.in eitherdirection. It is of interest that the German stand-ard for protective clothing against both vesicantswas only two hours 1 protection. Most of the experi-ments were carried out on various types of canvascloth coated with rubber on both sides. 50$ ofthe samples of this kind of material failed to givetwo hours* protection against ordinary mustard.

In the Spring of 1941 all work in the Dutchlaboratories was suddenly suspended and the labora-tories, including the remaining Dutch techniciansof the laboratory assistant grades, were leased tothe Delft Technical High School and usea as ordinaryteaching and research chemical laboratories. Sofar as Dr. Lenz was aware, no further work on chem-ical warfare was carried out.

Although no specific work on gas masks wascarried out by the Germans at Delft, Dr. Lenz knewthat the Germans were somewhat concerned at thehigh breathing resistance shown by the G.M.4O.

Throughout the occupation period the Germantroopr of all ranks, ana uniformed female auxil-iaries, in Oss invariably carried gas masks andLosantin tablets even v.hen off duty in the town.

After the midule of 1941 there was practicallyno pressure on the local Dutch population toobtain gas masks or to undertake any form of anti-gas precautions or exercises. The Dutch StateRailways continued to give considerable attentionto the problems and their employees were providedwith gas masks and instructed in their use. TheState Railways also had gas decontamination carsat every major railway station. These cars were,however, either constructed in 1939 or replicasof a type introduced at that time. Dr. Lenzthought that these activities were an independanteffort on the part of the Dutch State Railways rat-her than the result of German pressure or encourage-ment.

Dr. Lenz knew nothing of any C/VV activitiesby Sobering A.G., although this company had takenover Organon factories. This, however, cannot betaken as proof that Scherings are not manufacturingC/W material in German since they were veryreticient regarding most of their activities intheir home country. Dr. Lenz deduced that Soberingwere doing a certain amount of physiological re-search on G/Vv since he knew that their physiolo-gists had found that rats less than ten days oldgive no local reaction with "H". After this agea normal local reaction is shown.

The only specific C/W activities by theGermans in Holland, of which Dr. Lenz had any know-ledge, were the use of a few ten-litre bottles ofarsine which were dropped from an aeroplane in theneighbourhood of Greebe in daylight on 11th May1940. I questioned Dr. Lenz closely on this event,and he was quite sure that it had occurred andsaid that some of tnese containers had been sentto the Dutch C/\V laboratory at Delft for examina-tion. This experiment in C/Vv apparently caused noharm to anybody and was never repeated. In 1943the Germans took over a large laundry at Ubbergen,near Nijmegen, in order to convert it to a clothingdecontamination centre. A small gas testing labora-tory was also set up at this laundry.

No other information regarding German C/Vvactivities in Holland could be ascertained fromDr. Lenz or any other organisation in Holland.

Tat>le1.

Requirementsfor

Restartingof

Production

Nameofthe

Prod.capac»Raw

materialslabou-

Higherkgof

coaldaily

gas

Other

preparationper

week.

sufficientrers

staff

require1

in

per

requirements

.

for

(menor

theforaof

day

women)

steamelectr.

refrig.

l.Sulfanila-40kg

p.w.

3

1

200

perweek80

kg

of

midor

40

weeks

lammonia(fornr.2)

2.Sulfapyri-60kg

p.w.

6

2

25025

120andfromthe

10th

din

we600kgchlorsul-

fonacidand4001.

of

benzol(weekly)

3«Liverextr.'6000kgliver3

weeks12

I

900

run250

(Pemaemon)p.w.

4.VitaminD

i+0a50g

6-7weeks1

2

20

50

5.VitaminC

15kg

26

weeks9

2

500150

MethanolandNaOH

tobe

statedlater

B.Cholester-

on

ol(semi-6000kgraw1

week

4

600

100

manuf.)

material7«Nicotinic-

morethan

25m^

acid

700g

1

year

1

1

25

8.Pillingof

45

allkinds

10m3

of

ampoules

(girls)2

100l6o

i

9.Pharmaceut

30

2

150

packing3

3*mill

(girls)

10.Productionof

tablets11•

Manufacture

-

of

coated

7

1

50

60

tabl.

1

The

capacityofthe

Departments,mentionedunder

numbers8,9,

10and]

l1,

allowsfilling,

productionof

tabletsand

packingin

chargeof

thirdparties.

0

APPENDIX I.SCIENTIFIC AND TECHNICAL DEVELOPMENTS IN THE

PREPARATION OF SYNTHETIC HORMONES

Oxidation of Cholesterol:The oxidation of cholesterol-acetate dlbromide

is at present carried out in a homogeneous mixtureof acetic acid and ethylenedlchlorlde.

The result of this new procedure is a 50%Increased yield. This method is applied now byCiba (Basle), Sobering (Berlin) and Organon.

Desoxycorticosterone-acetate:The preparation of diazomethane is now possible

on a relatively large scale, and in consequence itis possible to prepare desoxycorticosterone-acetateon a technical scale. There are no fundamentalchanges from the original Reichsteln procedure forthe synthesis.

Progesterone:As the new oxidation-process of cholesterol

(see above) gives no pregnenolone-acetate, it wasnecessary to look out for a new preparation methodfor this substance. In the Sobering works theprocedure (which has been published by Butenandtc.s. in Berlchte) has started on a technical scale.With this method it is possible to reach a ZZ%yield of progesterone from Dehydro androsterone-acetate.

Ethinyl-testosterone;ifi'e preparation of ethlnyl-androstenediol is

now possible with other alcohols than tertiary butanol.

Synthetic Oestrone:It was very Important for Sobering to prepare

oestrone from another source than pregnant mares 1

urine.The chemists of Sobering, especially Inhdffen,

have.carried out the synthesis of oestrone startingfrom dehydro androsterone-acetate and as far as weknow this procedure has been applied on a technicalscale, (published in Berichte by Inhoffen),

The most difficult stage is the dehydrogenatingand demethylatlng of the first ring. Following thedata received from the German chemists the total yieldis between 10 and 20%•

As far as is known the whole procedure is not yetcarried out regularly in the factory.

APPENDIX II.PERISTON

This substitute for blood liouid was preparedby Weese and Hecht (pharmacological institute of theI. CL Farben), described in the publication : Hechtund Weese “Periston, ein neuer Blutflueslgkeitersatz n(Munch, med. Wschr. 90, 11 (1943) No.l.

It consists of a colloid, the polymerisation pro-duct polyvinylpyrrolldon (known as’ "Kollldon") In a2..$% solution, to'which Is added' NaCl, 0,9042^KOI, CaClo, 0,0005;* MgClg, 0,0024# NaHC03

“ andca. 10 vol. % free COo. This solution has a pH 6,and after being steritlzed is ready for use and keepsindefinitely. Tills product and similar mixtures ofslightly different composition are described collective-ly as "Periston". In the animal it.normalizes theblood pressure after an acute loss of blood. Itsaction persists for one or two days; after three tofour weeks the substance can no longer be detected inthe blood.

H Clinical experiences were published by Klees(Munch.Med. Wschr. 90, 29 (1943) No.2* According tothis author Periston is superior to all other knownplasma substitutes. He tested it in 50 oases ofhaemorrhage w mostly severe - (laparotomies, variousobstetrical cases); the doses varied from 100 to 700cm3. He observed a prompt restoration of normal bloodpressure without noxious Influences. The main actionsares-

(1) An analeptic action;

(2) A vasotonic action;

(3) An improvement of the capillary circulation.

Dieckhoff and Kunstler (Dtsch.Med.Wschr. 69, 589 (1943)No.33/34, obtained favourable results wltHPerlston inalimentary intoxication of sucklings.

Fonio "Blutersatz im Felde" (Sitz.ber.medlz.Bezlrksver-ein,' Bern-Stadt, Schweiz.med. Wschr. 73, 1416 (1943)No.47, remarks, concerning |f "das an der Ostfront verwend-ete Periston": "Die Akten uber die desselbensind noch nicht

|(abgeschlossen; Armeepathologen machen auf

Leber—Nlerensohadigungen aufmerksam".The last work has not yet been said about its action;

German army pathologists have called attention to liverand kidney damage.

APPENDIX III.APPLICATION OF CAPAIN IN SHOCK,

Literature: L. A. Gr. Hisslnk, Ned. TIJdschr.v. G-eneesk. 38, 52l (1944); 88,824 (1944).J. H. P. Jonxis. Maandschr. Kindergew.13, 169 (1944)

Capaln is an aoueous solution of the breakdownproducts of casein, obtained by the action of papainon this protein. It is characterised by its highcolloid©smotic pressure and its freedom from anaphy-lactogenic properties. It serves to retain fluid inthe blood streaA and also provides readily assimil-able nitrogen to the body.

It has been Issued for clinical purposes in100 cc. ampoules filled with a 15% solution of thecombination of these peptones and polypeptides.

A special type of capain is prepared for intrave-nous nitrogen feeding especially *for infants. Thesource of protein in this case consists of two partsof casein and one part of lactalbumen, to supply thenecessary amount of tryptophane and cystein.

Method of Application:

The usual dose of capain is from 75 to 150 cc.diluted with physiological saline, or 5% glucose solu-tion to 1 L. It is Injected intravenously, the rate ofthe injection depending on the condition of the patient.

In cases of shock, blood pressure is chosen as thecriterion, severe cases demanding a faster rate amountingup to 1 L per hour.

Results.

A review is given of twenty cases of more or lesssevere shock. The results of the treatment were satis-factory; only three of the patients died in the firstweek after the transfusion. Five of the patients had aslight general reaction (shivers).

With another twenty patients the author claims tohave obtained similar favourable results, but nodetails are given.

APPENDIX III (Continued)

Jonxis claims favourable results In Infantfeeding by the intravenous route* It is welltolerated and he gains the impression that capalnIs a complete protein substitute.

Method of Preparation

The following prescription is based on infor-mation obtained from Professor Brinkman of Groningen,who is the Inventor of capaln, and on limitedexperience in the Organon factory.

180 grs of sodium caseinate (soluble) aredissolved in 900 cc. of cold water. To this solutionis added a buffer solution of the composition:

40 vol. of citric acid 21 gr/I.60 vo'l. oBaikaline sodium phosphate (NagHP04 2

a a ) 35,6 gr/1.To this mixture 900 cc. of boiling water and

finally 12 gr of papain (l : 80) are added. The cloudysolution is stipred for ten hours at a temperature of60 to 70° C. The initial pH of the salution isapproximately 5.8. During the digestion much of thecasein dissolves but the cloudiness does not disappearcompletely. The solution is left overnight and aprecipitate of undigested material settles to the bottom.It is decanted or filtered. To the filtrate trichloro-acetic-acid is added to a final concentration of 3 g/100cc. The precipitate is filtered off through foldedfilters and the clear filtrate neutralised with 25#NaOH until Just red to Congo red. At this acidity thetrlchlore-aoetlc-acid is transformed into chloroformand sodium carbonate, provided the temperature 1b not toolow. It is found advantageous to keep the solution at60 to 70° C to promote the reaction. In case thesolution becomes alkaline it is neutralised by means ofcitric acid.

The solution is then concentrated in vacuo to one-third of its original volume. The temperature in theoriginal recipe was not specified but apparently 60 to70° C will do. At the end of the process the tempera-ture is raised to boiling point for a few minutes*Finally the solution is kept for two to three days atroom temperature. A slight precipitate which occasion-ally forms is filtered off through asbestos fibre orhyflo filters.

APPENDIX III (Continued)

The nitrogen content of the filtrate Is estimated.The strength of the solution Is. calculated bytaking 8 x the N-content. It is adjusted to 13 to

calculated back to protein. As a preservative270 nlpagln (p-oxy-benzolcacld methylester) is added.

It is Issued in 100 cc. ampoules. Before usethese ampoules must be carefully cleaned, preferablyby bichromate-sulphuric acid solution, follov/ed byfrequent washings with water. The last rinse shouldalways be one of freshly distilled apyrogenlc water.The filled ampoules are sterilized for one hour bylive steam.

Samples of the ampoules ready for issue aresubjected to a sterility test.

The toxicity in test animals is quite low; 5 cc'are well tolerated if slowly injected in the marginalearveln of a rabbit. No anaphylactic reactions areapparent in appropriate test on guinea pigs. Organonhave so far,prepared two batches only and thedefinite tests for. the toxicity have not yet beenestablished. Meanwhile the above-mentioned tests areused provisionally. Care should be taken to avoidthe development of micro-organisms during any stage ofthe process as subsequent sterilisation would stillleave dead bacterlas in the solution liable to causepyrogenic reactions.

APPENDIX IV.

VITAMIN C.

The shortage of vitamin C in German occupiedterritory and the impossibility of importingsufficient ouantlties, made it desirable to manu-facture vitamin C in Holland. As Hoffmann-1a-Rochewere unwilling to grant a licence a new processwas evolved. This starts from glucose and usesthe classical steps

sorbitol - sorbose - ketogulonic acid.

It avoids the use of potassium-permanganate and oflarge cuantities of acetone, both substances havingbeen very scarce in German-occupied countries. Asan oxidizing agent sodium-chlorate is used. Theconversion of sodlum-ketogulonate to ascorbic acidis performed with the aid of sodium fluoride. Thewhole process falls.cut side the scope of the Swisspatents, although this is still being contestedby Hoffman-la-Hoche.

The yields of ascorbic acid are considerablyinferior to those obtained by the Swiss process.The Dutch Government has stimulated research throughan official organisation and they too have found anew process ("which, to our mind, is partly dependenton the Swiss patents"). # Large scale production hasalso been taken up following this "Government-process ".

* Dr. Tausk f s comment.

APPENDIX V.

VITAMIN A.

In the course of experiments on a synthesis ofVitamin A the ketone I was prepared. From this sub-stance 1:.he methyl-ester of Vitamin A-acld II Is ob-tained by means of methyl-bromo-acetate and zinc inbenzene.

This acid possessed about one-tenth of thebiological activity of vitamin A itself.

The prospects for the preparation of Vitamin Afrom I, are good. As ester of the iso-vitamin Aacid II was also prepared. This substance was notactive.

ch3 ch3 ch3 0%X" GH « CH - C - CH - CH - CH - 0 » 0®c„33

Ich 3 ch3

CH « CH - C s CH - CH - CH - C « CH - COOH

II

CHg CH3jj - GH » CH - C = GH - C s GH - CH = CH - -COOK

III

APPENDIX VI.

HARFANIL HgN-HgO-OaOoNHgKg.rfg.nil (originally named Hesudln) was synthesizedby Klarer. On the basis of experiments with animalsIt was recommended by Domagk for the clinical treat-,ment of infections by anaerobic bacteria (e,g, gas-gangrene). In.the'animal the toleration is excellent.(Domap’k und Hegler. ‘'Chenotheraple bakteriellerInfektlonen H 2. Aufl., Leipslz 1942).

According to Hegler there is as yet (1942)little experience concerning the application In man.However, several Investigators have recommended thepreparation, amongst others Konjetzny. who used acombination with sulphanilanide (Prontalbin) locallyagainst wound Infection. This combination Marfan11-Prontalbln (l part M, 9 parts P) is supposed to beactive both against streptococci (and staphylococci)and anaeroblcs. The first publication concerningthis combination Is probably that by Beyer M DleChemotheraple In der Hand des Chirurgent Marfanll-Prontalbln, eln neues WundantlseptikumH (Zbl.Chir.68. 1730, 1941; not available In Oss).

Other Referencesit

Meull. H Zur Frage der Fruhbehandlung von Kriegsver-letzungen mlt SulfonamidenM

. (Schweiz.med. Wschr. 74,23, 1944). M. mentions that Klages (Med.Klin*1943.37/38) saw good results in war wounds with Marfanilfor the treatment and prophylaxis of gasgangrene.It is stated further that the combination Marfanll-Prontalbln has been recommended for war wounds byDomagk. Haferland. Konietzny and others (in localand oral application).Kirschner is sceptic about the benefit of M.P. Inthe treatment of wounds.

Florcken stresses the harmlessness of large dosesof U.P. powder, locally applied.

G. Herrmann f Marfan 11-Prontaiblnpuder In der'Krleg-lchirurgle (Munch. med f Wschr. 90, 697 (1943), No.48/49). H. reports on his experiences with theGerman army in Russia. He used the preparation formany different injuries. According to this authorthe locally,applied M.P. powder gives a chance ofsuccess in fresh wounds only (up to 12 hours afterthe injury)1 As to fresh wounds, H. advocatesuniversal application of M.P. powder (after primarywound excision).

APPENDIX VI. (continued)

H. W. Voigt ( SulphpnamIdes in surgery). (Dtsch.med.'Ws ;hr. 70, 93 (1944) No. 7/8). V. used, among otherpreparations, II.P. powder locally with very favour-able results.

H,Kr ue H Sulpho n amid e an der Front." (Dtsch.med.Wschr. 69, 417 (1943) No.2l/?2. K. saw good effectsof sulpHpnpmides (locally and orally) in the treat-ment of war wounds. He also mentions casually theuse of M. P.

Eunike. "Uber die lokale Anwendung (Jes Mar fan 11-Prontalbin in der ChlrJLrgle zur Bekampfung der Wund-infektion". Fortsohrltte der Theraple 18, 11 (1942)(not available in Oss).

Preparation of Marfanil:-

Formula HgM-HoG-< > 30,11 HoGerman Patent 7P.6336 (priority 27.1.39):

Protection for the reaction RCHg< >30oNHp—>NHpCH2<Z>S02NH2, executed in practically every Imaginableway. (R* a substituent which can be converted to theamino group). Included is also the reduction of /

%C-<I> S0 2NH2.rman Patent Application I 67614 (priority 8.8.40):

Halogenation of compounds with the formulaCH3 S02Hlg (HLg ss halogen) with halogenatlng agentsat Increased temperatures.

German Patent Application I 67629 (priority 8.8.40);

Reaction of compounds with the formulaSOoHlg (as produced by the preceding patent application)with ammonia at temperature below 60°C, thus producingHlgCHo S°2 NH2

TIPAT IN (l.G. Farben).

Formula 0gHioCC«N- < > S0o-<CZ>- Ng CgH-| oQ 5(digalactoside of dlaralnodiphenvl

sulfone)No particulars about the preparation available.

APPENDIX VI (Continued)

German Patent 694679 (priority 21.10.38):

Preparation of stable solutions of compoundslike Tlbatln, by addition of sugars to the solu-tion. In an example the addition of Invertedlactose to a solution of Tibatin is mentioned.

APPENDIX VII

DOLANTIN.Chlorhydrate of l-methyl-4-phenylplperldln-4-carbon-

icacld-ethyl-ester. Tabl. 25 mg, amp. 100 mg.

No information was available at Organon regard-ing the manufacture of Dolantin. The followingreferences to its use had been filed in the Organonscientific library

Schlungbaum (lied.Klin. 35, 1259, 1939).

Dolantin opuses no addiction, no habituation.

Skamnakis (Zbl.Gynak. 67, 139.7, 1943).

Dolantin is frequently used in obstetrics asan analgesic. The author has recently replacedDolantin by the "Analgetlcum 446” bayer, the latterhaving a better spasmolytic and analgesic action(no details on the latter.preparation).

>

v* Brucke (Wien.kiln. Wschr. 1940 II, 854; ref Klin*Wsohr. 22, 59, 1941).

Dolantin gives rise to addiction in predisposedindividuals; therefore one has to be cautious inprescribing this preparation.

Kucher. M Zwei Falle von Dolantinsucht * (Klin.Wschr.19, 688, 1940).

Describes two cases of pronounced addiction(high dosos; up to 25 amp. s 2,5 g pro die. 1 ).This should be a warning, as most cliniciansdeny that there can be such a thing as addictionto Dolantin. The author emphasizes, the Importanceof this “ersatz” for morphine, the necessary rawmaterial being available in.Germany.

G-arratal et al. (ref. Schweiz, med* Wschr. 73, 83,1943).Prolonged use of Dolantin leads to habituation.

Oelkers and Wanowius (Klin. Wschr. 21, 752, 1942) demon-strated in micean increase of'toxicity of various

substances, among which Dolantln, when the animals weretreated with eulphonanldes. This might be importantfor therapeutics in man.

APPENDIX VIII

SESAROL.

The drug Is a poison for allkinds of Insects# It works bysimply contact with the animal.It Is scarcely soluble In waterbut to a large extent In lip-old solvents. Therefore, ItIs easily absorbed by the lip-

oids in the cutlcula of Insects. It reaches the nerveendings and because it Is a typical nerve poisonkills the animals under violent spasms. The skin ofmammals is not permeable for G-esarol, therefore notoxic effects are to be expected In these animals.Because contact with the skin is necessary, G-esarolis more active against flies, mosquitos, moths, etc#than against hairy animals like caterpillars.

H

CCI 3

best be applied by making a solution,e.g. in‘carbontetrachlorlde, and spraying this on thewalls of the room, on the floor, on leaves of plants,etc. Very small amounts suffice, a stable could bekept free from flies for five to six we 3kg with anamount of five to seven g pro cm2.

To kill a rat of about 60 grams an amount of25 mg given orally is necessary, mice of about 20grams body weight can be killed with 20 mg.

The effect is not immediate, a lag time (forresorption) is present, depending on the species ofanimal.

A good survey of G-esarol and related drugs canbe found in Helv.chlm.acta. £7, 892, (1944).

APPENDIX IX

PENICILLIN

The Organon specialists knew nothing of anylarge scale manufacture of penicillin in Germany.It will of course be known in England, that Clbaof Bale has taken up the manufacture of this prod-uct. Reports were published in a special issueof the Schweiz. Med. Wschr. 74, No.23, (1944).

From private information they know thatSobering were engaged on rather Intensive researchon penicillin. On various occasions they obtainedstrains of penicillium notatum from ProfessorWesterdijk of Baarn, who is in charge of the HCen-traal Bureau voor Schimmelcultures H

, having at itsdisposal what is probably the largest collectionof moulds of the world. From discussions withProfessor Westerdijk the impression was gatheredthat the strains of penicillium notatum, availablein Holland and delivered to Sobering, were probablyInactive as regards penicillin-formation. It isunderstood that the fluid of their cultures is blue.

On the other hand Professor Julius, collab-orating with Dr. Tausk of Organon and with ProfessorWesterdijk, took up penicillin research secretly.Unis has never been brought to the notice of theGerman wartime managers of Organon, A strain ofmoulds was found, giving a high yield of a veryactive anti-bacterial substance. It cannot yet besaid whether this is identical with penicillin, al-though in many respects it behaved exactly like it.

Other Dutch centres of research have recentlybecome actively interested in penicillin and otheranti-bacterial substances of moulds. It is believedthat none has got so far as Professor Julius and hiscollaborators.

APPENDIX X.

1st of Shortages

(alphabetically arranged)

Acetic Acid; Delivery almost stopped afterthe Amsterdam factory had beendamaged. In 1944 we receivedthree tank loads from Germany.

Acetone: First years, of the war almostunobtainable. Later on a spe-cial permit.

Acetylsalicylic Acid: Limited import from Germany Inbulk.

Ethyl Alcohol: Though rather scarce alwaysobtainable.

Aneurlne; Irregular though sufficientdeliveries from Germany andHungary.

Asbestos Filters: (Seitz). Almost unobtainable.

Benzaldehyde; Sporadic supplies.

Boron Compounds unobtainable. The last batches ofampoules received from Germanywere of boronfree glass of verypoor ouality.

Chinydron; Very difficult. Chromium saltsnad to be handed. In exchange( I. G.) •

Chloroform; Very limited.

Chloro-suLohonlc Ac Id: Obtainable though restricted.

Chromic Acid; Very short.

Code In: Not available.

Cod liver oil; Unobtainable.

Coffeine and its salts: Mot available In. Germany.Small stocks in Holland. Germansattempted a synthesis.

APPENDIX X (Continued)

Dlchloro-ethylene; In Holland unobtainable. X. G,Farben delivered smallQuantities but Informed usJust before the liberationthat they were unable tocontinue.

Dimethylsulphate; Unobtainable,

Glass Apparatus; Orders for laboratory glass-ware delivered after severalyears or not at all.Particularly funnels arunobtainable.

Glycerine; Though liable to restrictions,available in modest quantities.

Iodine; Compounds very scarce.

Iron Ammonium Citrate; Almost unobtainable.Manganese sulphate; Not available.

Papalne; Unobtainable.

Papavarine; Delivered only once.

Peanut Oil; Completely exhausted.Phenacetln; Unobtainable.

Potassium Permanganate; Not available.

Haney metal; After the bombing of the fac-tory, unobtainable.

Sodium Benzoate; Supplied In small Quantities.

Sodium Fluoride; Not available.

Sulphuric Acid; Decreasing delivery.

Semlcarbazlde; We have the impression thatthe last stocks sire exhausted.

Tartaric Acid; Unobtainable.

Trlchloro-acetic Acid; Not available.

All fine chemicals for analytical purposes were verydifficult to. obtain, or were not delivered at all.

Iodine;

Papaine;