Part I synthesis of some new local anesthetics. Part II carbohydrate degradation by Sarcinae Lutea

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U n p u b l i s h e d t h e s e s s u b m i t t e d f o r t he M a s t e r ' s a n d D o c t o r ’ s d e g r e e s a n d d e p o s i t e d in t h e N o r t h w e s t e r n U n i v e r s i t y L i b r a r y a r e o p e n f o r i n s p e c t i o n , b u t a r e to be u s e d o n l y w i t h d u o r e g a r d to t h e r i g h t s o f t h e a u t h o r s . Bibliographical r e f e r e n c e s m a y be n o t e d , b u t p a s s a g e s m a y be c o p i e d o n l y w i t h t h e p e r m i s s i o n o f t h e a u t h o r , a n d p r o p e r c r e d i t m u s t be g i v e n in s u b s e q u e n t w r i t t e n o r p u b l i s h e d w o r k . E x t e n s i v e c o p y i n g or p u b l i c a t i o n o f t h e t h e s e s in w h o l e or in p a r t r e q u i r e s a l s o t h e c o n s e n t o f t h e D e a n o f t h e G r a d u a t e S c h o o l of N o r t h w e s t e r n University. _ T h i s t h e s i s by h a s b e e n u s e d b y t h e foll^tflng a t t e s t t h e i r a c c e p t a n c e of t h e




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The author wishes to express his appreciation to Dr* L. S. Fosdick for his encouragement and guidance throughout the course of this work*



SYNTHESIS OF SOME NEW LOCAL ANESTHETICS INTRODUCTION.................................. 1 (A) SYNTHESIS OF THE NORMAL AND ALKAMINE ESTERS OF m-AMIN OMAN DELIC ACID Statement of Problem. ............... 8 9 Experimental Procedure and Results......... Preparation of m-Nitrobenzaldehyde........ 13 Preparation of m-Nitromandelonitrile 14 Preparation of Alkyl Esters of m-Nitromandelic A c i d ...................... 14 Methyl m-nitromandelate.................... 15 n-Propyl m-nitromandelate.................. 15 iso-Propyl m-nitromandelate.............. 15 n-Butyl m-nitromandelate*.................. 15 p-Chloroethyl m-nitromandelate. ........ 16 Preparation of Alkyl Esters of m-Aminomandelic A c i d ....................... 16 Methyl m-aminomandelate........... 17 Ethyl m-aminomandelate ........... 17 n-Propyl m-aminomandelate................ 17 ......... 17 iso-Propyl m-aminomandelate n-Butyl m-aminomandelate. ............ 18 p-Chloroethyl m-aminomandelate......... 18 Preparation of Alkamine Ester of m-Aminomandelic Acid....................... 18 Discussion and Conclusions.................. 19 Summary ......... ••••................. 20 (B) SYNTHESIS OF THE NORMAL AND ALKAMINE ESTERS OF 4-AMIN0IS0PHTHALIC ACID Statement of Problem............ 21 Experimental Procedure and Results••.••••.. 22 Preparation of 4-Acetamino-l,3-dimethy1benzene........................ 25 Preparation of 4-Aeetaminoisophthalic Acid........................ 25 Preparation of Esters of 4-Aminoisophthalic Acid. ••••.••........ 26 n-Dipropyl-4-aminoisophthalate.......... 27 P-Chloroe thy 1-4-amino isophthal a t e ....... 27 y-Chioropropy1-4-aminoisophthalate..... 27 Preparation of Alkamine Esters of 4-Amlnoisophthalate ...... 28 Diethylaminoethyl-4-aminoisophthalate.• 29 Dipropylaminoe thy1 -4-aminoi s ophthalate.............................. 29 Dibutylaminoethyl-4-aminoisophthalate•* 30

Diethylaminopropyl-4-aminois ophthalate............................ Dipropylaminopropy1-4-aminoisophthalate................... ........ Dibutylaminopropy1-4-aminoi sophthalate............................ Preparation of 4-Nitro-m-xylene. ....... Preparation of 4-Nitroisophthalic Acid. Preparation of 4-Nitroisophthalyl chloride * ........ ..................... Preparation of Diethylaminoethyl-4nitroisophthalate Hydrochloride.....« Preparation of Diethylaminoethyl-4aminoisophthalate Hydrochloride..*.*• Discussion and Conclusions........... Summary........ (C) SYNTHESIS OF THE DIALKYLAMINOALKYL ESTERS OF 4-FLU0R0IS0PHTHALIC ACID Statement of Problem.................. Experimental Procedure and Results....... Preparation of 4-Fluoro-l,3-dimethyl......................... benzene Preparation of 4-Fluoroisophthalic Aci d . . ................................. Preparation of 4-Fluoroisophthalyl chloride...... Preparation of Hydrochlorides of Dialkylaminoalkyl-4-fluoroisophthalates Diethylaminoethyl-4-fluoroisophthalate hydrochloride............ Dipropylaminoethyl-4-fluoroisophthalate hydrochloride.......... Dibutylaminoethy1-4-fluoroisophthalate hydrochloride ......... Diethylaminopropyl-4-fluoroisophthalate h y d r o c h l o r i d e Dipropylaminopropyl-4-fluoroisophthalate hydrochloride............ Dibutylaminopropy1-4-fluoroisophthalate hydrochloride ........ Discussion and Conclusions................ Summary....................................


CARBOHYDRATE DEGRADATION BY SARCINAE LUTEA Introduction ............ ......... . Statement of Problem...................... Experimental Procedure and Results........ Phosphorylation ofGlucose.............. Table I .......................

30 30 30 31 31 32 32 33 34 35

37 37 40 41 4l 42 42 43 43 43 44 44 44 45

46 55 59 60 6la

Production of Phosphoglyceric A c i d 62 63 Table I I ................................ Degradation of Phosphoglyceric Acid.... 63 Table I I I ............................... 65 Reduction of Pyruvic Acid to Lactic Acid. ....................... Table I V ............................... 67a Discussion and Conclusions................. 68 Summary ...................... 70 Bibliography ....................... 71





The problem of the relation between chemical constitution and physiological activity has been widely studied, and, since the discovery of procaine by E i n h o m a. and Uhlfelder in 1909, much of this work has been done in the field of local anesthetics.

In spite of a great

deal of cooperative effort between the organic chemist and pharmacologist, no local anesthetic has been prepared which has had a sufficient number of local anesthetic properties superior to procaine to completely replace it in clinical use. Although the goal - the production of a perfect local anesthetic - has not been reached, a great deal of data regarding structure and anesthetic activity have been compiled.

Much of this material has been adequate­

ly summarized in several excellent reviews written by 2 3 4 6 Hirschfelder and Bieter, Cook, May and Dyson and others. On examination of the structure of procaine, one may readily see several changes that can be made in the procaine molecule which might yield Interesting (1) Einhorn and Uhlfelder, Ann., 3?1» 131 (1909) ( 2 ) Hirschfelder and Bieter, Physiol. Rev., 1 2 , 1 9 0 ( 1 9 3 2 ) (3) Cook, Studies Inst. Divi Thomae, 2, 6 3 - 1 0 0 ( 1 9 3 8 ) (4) May and Dyson, 'The Chemistry of Synthetic Drugs (5) Schaumann, Arch, exptl. Path. Pharmakol, 190* 30-51 T1938) Whitacre, Anesthesia and Analgesia, 1 8 , 112 (1939) Bernard!, Ann. Chim. form., Aug., 68-115 (1939)

2 results:



0 C - COOC s H 4N




One or a combination of several of the following changes can be accomplished: The amino group can be shifted from the para position to the ortho or meta positions, or can be alky­ lated or acylated* The length of the side chain can be increased, and the ethyl groups of the alkamine residue can be re­ placed by other alkyl groups or aromatic groups* The amino group can be replaced by such groups as alkoxy, thioalkyl and the halogens* Groups can be introduced between the carboxyl group and the aromatic nucleus* The benzene ring itself can be replaced by such heterocyclic nuclei as furan, pyrrole and thiophene* Shifting the amino group to either the ortho or meta position of the alkamine esters of aminobenzoic £ acid was found to decrease the anesthetic efficiency* The same was found to be true of the cinnamic acid esters 7


by Wildman and Thorp, and also by Friedlander* Kamm reached the conclusion that the introduction of a chain of three carbon atoms between oxygen and (6) Kamm, J* Am. Chem. Soc*, 42, 1030 (1920) (7) Wildman and Thorp, U* S* Patent 1,193*649 (1916) (8) Friedlander, 8, 1007* D.R.P* 187,593

3 nitrogen in the side chain increases hoth the anesthe­ tic activity and toxicity.

This is also true if the

size of the alkyl groups of the alkamine residue is increased.

These generalities apparently cannot he

extended to compounds that do not have the henzene ring 9

as a nucleus, because Walters and McElvain, working with piperidine derivatives, have found that the long duration of anesthesia is associated only with those compounds which contain a PhCHg or PhCHgCHg substituent in the two position of the piperidine nucleus.


creasing the length of the carbon chain which separates the phenyl group from the nitrogen atom to more than three carbon atoms, or decreasing It to one carbon atom, decreases the anesthetic activity. In the synthesis of thiocaine, Hansen and Fosj dick



replaced the ester oxygen

with sulfur and found that it was

of the carboxyl group more toxic and had a

! greater anesthetic efficiency than procaine. |


The amino group has been replaced by various

I halogens.

Coles and Lott


have used chlorine and

j Iodine, but no definite conclusions could be reached


j to anesthetic potency. Fluorine has been used by Fosdick a. s I and Campaigne, who prepared the alkamine esters of

i 1 i


(9) Walters and McElvain, J. Am.

Chem. Soc., 5£, 4625 (1933)

( 1 0 ) Hansen and Fosdick, ibid, 2872 (1 9 3 3 ) ( 1 1 ) Coles and Lott, ibid, ^ 8 , 1 9 3 9 ( 1 9 3 6 ) ( 1 2 ) Fosdick and Campaigne, ibid, 6 5 , 9 7 4 (1 9 4 1 )

! p-fluorobenzoic acid and found that they were from onej | third to one-ninth as toxic as procaine, and their anesj

thetic efficiency was equal to, and, in some instances, greater than procaine, but these compounds were very


I irritating.

Rohmann and Scheurle


prepared the alka­

mine esters of p-hydroxybenzoic acid and p-alkoxybenzoic acids.

The esters of the first series of compounds were

very toxic, but etherification of the hydroxyl group de­ creased the toxicity, as well as the anesthetic efficien­ cy.

By increasing the size of the alkyl group in the

ether linkage the toxicity and the anesthetic efficiency were increased.

Donleavy and English


prepared a series

of thioalkyl benzoates, and preliminary pharmacological investigation has shown these compounds to possess marked local anesthetic activity and low toxicity.

Contrary to

most observations, they found that the ortho and meta compounds were more active than the corresponding para derivatives. Alkyl and dialkyl amides of p-aminobenzoic acid


have been shown to be strong surface anesthetics.

The benzene ring has been replaced by other ring systems.

Gilman and Pickens


prepared the procaine

analogs of pyrrole, furan and thiophene and studied their (13) Rohmann and Scheurle, Arch. Pharm., 274. 110 (1931) (14) Donleavy and English, J. Am. Chem. Soc., 62, 220 TT9A0 ) (15) Wenker, ibid, 60, 1081 (1938) (16) Gilman and Pickens, ibid, 4£, 245 (1925)

5 anesthetie efficiency.

In the order of increasing ac­

tivity the compounds were listed as follows: thiophene, pyrrole and benzene.


If compared on the

basis of aromaticity, the order seems to be reversed, the aromaticity decreasing as the anesthetic efficiency increases - aromaticity being defined as the extent of electronegativity that a group possesses. 17

Esters of amino napthoic acid

showed an ac­

tivity comparable to cocaine, but the toxicity was less. Other experiments using napthalene as a nucleus have been 16

reported. 19

Phatak and Emerson

prepared various alkyl

esters of 2-furoic acid, and these compounds had approxi­ mately the same activity as cocaine.

In a later study

Phatak found that by 5-alkyl substitution in the furan ring the anesthetic activity was lost.

Dialkylamino so furoates were prepared by Cook and Kreke as topical

anesthetics. Recently a great deal of work has been done on heterocyclic compounds containing more than one heterosi cyclic atom. Kaufmann and Schulz prepared a series of (17) Houston, Proc. Oklahoma Acad. Sci., 14, 77 (1934) (18) Fisk and Underhill, J. Pharmacol., 4£, 329 (1933) Sergievska and Nesvad'ba, Russ*, 45, 289, Dec. 31, 1935 Sergievska and Nesvad'ba, J. Gen. Chem., (USSR) 8, 924 (1938) Blicke and Parke, J. Am. Chem. Soc., 61, 1200 (1939) (19) Phatak, J. Pharmacol., ^3, 174 (1936) Phatak, Univ. Calif. Pub. Pharmacol., 1, 55 (1938) (20) Cook and Kreke, J. Am. Chem. Soc., 6 2 , 1951 (1940) (21) Kaufmann and Schulz, Arch. Pharm., 273. 31 (1935)

6 benzothiazolylureas which had anesthetic action.


zoline derivatives have been shown to be two and a half 82 9 S 3

times as potent as procaine, but three times as toxic. Certain type® of oxazoline compounds have been covered in 24

a patent,

but no report concerning the anesthetic ac­

tivity of these compounds has been published.

The same 26

is true of a series of alkoxy-2-aminobenzothiazoles. Pyrazoline local anesthetics, which are derivatives of benzylideneacetone and alkylated 3,4-dihydroxybenzyli26

deneacetone, have been prepared by Nisbet*

These com­

pounds were more potent than cocaine in producing topical anesthesia of the rabbit*s cornea and were very powerful when injected intracutaneously.

Hone of the pyrazolines

was irritating, and the toxicities were less than that of 27


Bloom and Day

prepared a series of 2-alky1-

aminobenzimidazoles as anesthetics, but no results of 28 physiological tests were given. Hart synthesized 5methyl- and 5,5-dimethylthiazolinephenol derivatives that had local anesthetic properties and relatively low toxi29

city. (22) (23) (24) (25) (26)

In an extensive investigation Burtner and Lehmann

Sinha, J. Pharmacol., 2L, 199 (1936) Sinha, ibid, 66, 54 (1939) Englemann, U. S. Patent 2,027,031 Englemann, U. S. Patent 2,019,529 Nisbet, J. Chem. Soc., 1237 (1938) Nisbet, ibid, 1568 (1938) (27) Bloom and Day, J. Org. Chem., 4, 14 (1939) (28) Hart and Niederl, J. Am. Chem. Soc., 61, 1145 (1939) (29) Burtner and Lehmann, ibid, 6 2 , 527 (195-0)

!j prepared derivatives of carbazole, dibenzofuran and di­


j benzothiophene derivatives*

They found that the best

J compound of the series was @-diethylamino ethyl-5-ethyl!i I carbazole-3-carboxylate hydrochloride, which was more than three times as potent as cocaine and only twenty I | percent as toxic* The activity of these compounds ap • O

£> • 05 d

•H o O P

d CO CD d d O l>s M Ph

d © £ d O ft d O O *H P O A

d © £ d O

ft © d {>5 ft © d rH aJ P © o ra

d o


ft s

ft o o p © d d ©


d © ft

o © ft > d a o o o o d © •H aoO +5 ‘H d > o © d •H o d P d Jps• O © ft ft 3



Diacuasion and Conclusions

This investigation has demonstrated that Sarcinae Lutea contains the necessary enzyme systems to form lactic acid from carbohydrates*

There was a marked difference

in the rates of reactions of the various steps studied. The phosphorylation reaction was slow and did not occur at all at a pH of 5*4 or 8.8, even after the reaction had been allowed to proceed for eight hours.

The step

involving the formation of phosphoglyeerie acid was quite rapid, and occurred to a marked extent at pH 6.6.


this pH level the amount of barium phosphoglycerate re­ covered was at least ten times greater than at the other pH levels studied.

The same sort of picture was obtained

with the next step in which the amounts of phosphoric acid, pyruvic acid and acetaldehyde produced by the breakdown of phosphoglyeerie acid were determined.


final reaction studied - the reduction of pyruvic acid to lactic acid - confirmed the observation made by Fosdick, 44

Hansen and Wessinger Sarcinae Lutea is low.

that the reductase activity of A large part of the pyruvic acid

was lost in the reaction, but the amounts of lactic acid and acetaldehyde recovered were much less than the theoreti(44) Fosdick, Hansen and Wessinger, J. Am. Dent. Assoc., 24, 1445 (1937)

69 cal yield based on the amount of pyruvic acid decomposed. If one compares the action of Sarcinae Lutea, yeast and Bacillus Acidophilus,

It is apparent that all

these organisms contain the enzyme systems necessary for the degradation of carbohydrates, but in different amounts* Sarcinae Lutea is much less active than yeast in the phosphorylation reaction, but has about the same activity as Lactobacillus Acidophilus at pH 5.4 and 6.6 and less at pH 8.8. The formation of phosphoglyceric acid by Sarcinae Lutea at pH 6.6 is greater than that of yeast or Lacto­ bacillus Acidophilus. Sarcinae Lutea forms more pyruvic acid than Lactobacillus Acidophilus and produces approximately the same amount as yeast at pH 6.6, but less than yeast at pH 5.4 and 8.6.

Sarcinae Lutea produces less acetalde­

hyde than these other organisms at all pH levels studied. The reduction of pyruvic acid to lactic acid by Sarcinae Lutea is much slower and less than by yeast or Lactobacillus Acidophilus. |

These observations indicate that the role played by Sarcinae Lutea in the production of lactic acid in the mouth is a minor one.

This organism has very little


effect on the phosphorylation of carbohydrates to iniii-


ate the reaction of acid formation and on the reduction of pyruvic acid to lactic acid to terminate the reaction.

TO It becomes apparent that the only reactions which Sarcinae Lutea is capable of* catalyzing are the reactions In which phosphoglyceric acid and pyruvic acid are formed, and these only to any marked degree at pH 6.6, which is in the pH range found in the mouth.

Therefore, any symbiotic

effect of Sarcinae Lutea must occur in these two reactions.



Sarcinae Lutea has been found to contain the

necessary enzymes for the formation of lactic acid from glucose• 2.

The reactions of carbohydrate degradation by

Sarcinae Lutea take place at different rates,


that the enzymes are present in varying amounts. 3*

The reactions of phosphorylation of glucose and

reduction of pyruvic acid by Sarcinae Lutea are slower than with yeast and Lactobacillus Acidophilus. Sarcinae Lutea in the presence of other organ­ isms may aid in the production of lactic acid and, fore,

in the decalcification of teeth.



gage 39 22 1 13 5 6 9 6 1 5 3 4 37 1 6 6 10 5 3 8 2 13 9 4 3 6 9 1 5 2 5 8 10 22 1 22 6 6 16 5 5


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1 38 5 5

8 6 6 24 26 25 3 ! 4 22

26 1 2


60 47 56 48 58 47 46 57 49

60 57

58 59

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(19^0 )

73 Page



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48 48

60 54 47 46 4? 55 49 56 57 49 54 55 48 55 47 47 48 47



Name Joseph Calandra

Bom March 17, 1917 Chicago, Illinois

Education McKinley High School, Chicago, Illinois - 1934 Illinois Institute of Technology - 3.S. 1938

Organizations Sigma Xi Phi Lambda Upsilon American Chemical Society

Positions Assistant in Chemistry - Illinois Institute of Technology - 1935-1938 Assistant in Chemistry - Northwestern University Dental School - 1938-1942

Publications 'Some Alkyl and Alkamine Esters of m-Aminomandelic Acid and Related Compounds' with L. S. Fosdick - J. Am. Chem. Soc«, 6J, 1101 (1941) 'The Toxicity of Sulphated Higher Alcohols' with E. H. Hatton and L. S. Fosdick Journ. of Dent. Res., 1 9 . 87 (1940)